The Mast Cell. A Multifunctional Effector Cell 978-3-030-24189-6, 978-3-030-24190-2

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Domenico Ribatti

The Mast Cell A Multifunctional Effector Cell

The Mast Cell

Domenico Ribatti

The Mast Cell A Multifunctional Effector Cell

123

Domenico Ribatti Department of Biomedical Sciences, Neurosciences, and Sensory Organs University of Bari Bari, Italy

ISBN 978-3-030-24189-6 ISBN 978-3-030-24190-2 https://doi.org/10.1007/978-3-030-24190-2

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© Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Mast Cell Ontogeny . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 First Evidence of Bone Marrow Origin . . . . . . . . . . . . . 2.3 Development of Mast Cells Along the Myeloid Pathway 2.4 Stem Cell Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Integrins and Cell-Adhesion Molecules . . . . . . . . . . . . . 2.6 Chemokine Receptors and Interleukins . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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The Staining of Mast Cells . . 3.1 Background . . . . . . . . . 3.2 Metachromasia . . . . . . . 3.3 Alcian Blue-Safranin . . 3.4 The Tyrosine Kinase Kit 3.5 Tryptase and Chymase . 3.6 Other Stainings . . . . . . References . . . . . . . . . . . . . . .

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Mast Cell Heterogeneity . . . . . . . . . 4.1 Background . . . . . . . . . . . . . . 4.2 Mast Cells in Thymus . . . . . . 4.3 Mast Cells in Duodenum . . . . 4.4 Mast Cells in Mammary Gland 4.5 Other Localizations . . . . . . . . 4.6 Mechanistic Insights . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

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Mast Cell Biology and Functions . . . . . . . . . 5.1 Background . . . . . . . . . . . . . . . . . . . . . 5.2 Mast Cell-Derived Secretory Products . . 5.3 Mast Cell Immunological Functions . . . 5.4 Mast Cell Non-immunological Functions References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Mast Cells in Arteriogenesis . . . . . . . . . . . . . . . . . . . . . . 6.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Factors Involved in Angiogenesis and Arteriogenesis 6.3 Inflammatory Cells in Arteriogenesis . . . . . . . . . . . . 6.4 Mast Cells in Arteriogenesis . . . . . . . . . . . . . . . . . . 6.5 Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Mast Cells in Primary Systemic Vasculitides . . . . . . . . 7.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 Experimental Evidence of the Involvement of Mast Cells in Vasculitides . . . . . . . . . . . . . . . . 7.3 Clinical Evidence of the Involvement of Mast Cells in Vasculitides . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4 Therapeutic Perspectives . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Mast Cells in Blood-Brain Barrier Alterations and Neurodegenerative Diseases . . . . . . . . . . . . . . . . 8.1 The Blood-Brain Barrier . . . . . . . . . . . . . . . . . . 8.2 Mast Cells in the Brain . . . . . . . . . . . . . . . . . . 8.3 Mast Cells in Cerebral Ischemia . . . . . . . . . . . . 8.4 Mast Cells in Multiple Sclerosis . . . . . . . . . . . . 8.5 Mast Cells in Angiogenesis Occurring in Disease with Blood-Brain Barrier Alterations . . . . . . . . . 8.6 Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Mast Cells and Basophils: A Link Between Angiogenesis and Inflammation in Allergic Diseases . . . . . . . . . . . . . . . . . 9.1 General Biology and Mediators of Mast Cells and Basophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 Mast Cells and Basophils in Allergy . . . . . . . . . . . . . . . 9.3 Mast Cells and Basophils in Inflammation, Angiogenesis and Tissue Remodelling . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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10 Mast Cells in Tumor Fate . . . . . . . . . . . . . . . . . . . 10.1 Tumor Microenvironment . . . . . . . . . . . . . . . . 10.2 Mast Cells and Tumor Growth: Pros and Cons References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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11 Mast Cells in Tumor Angiogenesis and Lymphangiogenesis 11.1 Mediators Released by Human Mast Cells Involved in the Angiogenic Response . . . . . . . . . . . . . . . . . . . . 11.2 The CAM Assay in the Study of Mast Cell Induced Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3 Mast Cells in Experimental Tumor Angiogenesis . . . . . 11.4 Mast Cells and Angiogenesis in Solid Tumors . . . . . . . 11.5 Mast Cells and Angiogenesis in Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.6 Mast Cells and Tumor Lymphangiogenesis . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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12 Mast Cells as Therapeutic Target in Cancer 12.1 Background . . . . . . . . . . . . . . . . . . . . . 12.2 Inhibition of the SCF/Kit Axis . . . . . . . 12.3 Tyrosine-Kinase Inhibitors . . . . . . . . . . 12.4 Other Molecules . . . . . . . . . . . . . . . . . 12.5 Perspectives . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Chapter 1

Introduction

Although mast cells have been identified over 170 years ago, their physiological role in the body has remained a mystery. Since ancient times, mast cells have probably been part of protective mechanisms. Their original function, indeed, is to be found in parasite and bacterial defence of the host, and as a general inducer of inflammation (Bischoff 2009). This early type of cell has differentiated toward a more complex cellular entity involved in different regulatory processes, such as immunomodulation, tissue repair and remodelling after injury, angiogenesis, and possibly other biological functions (Ribatti and Crivellato 2009). Mast cells are present in all classes of Vertebrates and have emerged >500 million years ago, long before the development of adaptive immunity (Crivellato and Ribatti 2010). Mast cells with dendritic cells and monocytes represent one of the first cells of the immune system to interact with environmental antigens and allergens or environmental-derived toxins. Mast cells are long-lived and survive in body tissues for months or even years, involved in innate and adaptive immunity (Westerberg et al. 2015). It is likely that a complex interplay between mast cells and surrounding cells, mediators, and extracellular matrix proteins ensure the prolonged survival of tissue mast cells (Metcalfe et al. 1997). Mast cells are localized at the junction point of the host and external environment at places of entry of antigen (gastrointestinal tract, skin, respiratory epithelium). In humans, mast cells have been described to reach densities of up 500–4000 per mm3 in the lungs, 7000–12,000 per mm3 in the skin, and 20,000 per mm3 in the gastrointestinal tract. The selective placement of mast cells near the vasculature may ensure that the release of mast cell-derived pro-inflammatory products has instantaneous effects on the endothelium. Mast cells are heterogeneous in multiple aspects of phenotype and function, in relationship with animal species, anatomical location, stage of development and influence of genetic and microenvironmental factors. Because mast cell maturation is influenced by local microenvironmental factors, different mast cell phenotypes can develop in different tissues and in different locations of the same tissue. Mature mast cells express on their plasma membranes numerous receptors, which after binding © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_1

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of the corresponding ligands, can induce activation leading to the release of various inflammatory mediators. Mast cells are the primary effector cell mediating the pathophysiology of allergic diseases, which is attributable to the presence of high-affinity receptors for IgE on their cell-surface membranes and their intrinsic capacity to release significant amounts of pro-inflammatory mediators. Mast cells have multiple role extending for beyond their classical role in IgEmediated allergic reactions. Although mast cells secrete many pro-inflammatory agents including histamine, proteases, prostanoids, leukotrienes, and cytokines, they also release many anti-inflammatory agents. Mast cells can change from protective immune cells to potent pro-inflammatory cells which influence the progression of many pathological conditions, including autoimmune diseases and tumors. The role of mast cells in tumor biology is controversial due to the variety of processes they are involved in enacting both pro- and anti-tumorigenic effects depending on the context. When mast cells are activated, they degranulate releasing a wide range of already stored mediators, including histamine, serotonin, tumor necrosis factor alpha (TNF-α), proteoglycans and various proteases, and/or secrete newly synthesized lipid derivatives, cytokines, and chemokines. In this context, mast cells are involved in the regulation of the functions of many organs and tissues. Mast cell functions have been studied in vivo by using different models of mast cell deficiency or by using in vitro systems of both human and murine mast cells. In 1988, the first human mast cell line, HMC-1, was established from peripheral blood of a patient with mast cell leukemia (Butterfield et al. 1988). The use of mast cell-deficient mice and their reconstitution with bone marrow mast cells represent a powerful tool to study mast cells in vivo (Grimbaldeston et al. 2005). Moreover, another important tool in the study of mast cells is represented by the mast cell knock-in mice, i.e. mice that are genetically mast cell deficient due to abnormalities in c-kit structure or expression, but which have been selectively engrafted with in vitro-derived normal or genetically-altered mast cells.

References Bischoff SC (2009) Physiological and Pathophysiological functions of intestinal mast cells. Semin Immunopathol 31:185–205 Butterfield JH, Weiler D, Dewald G et al (1988) Establishment of an immature mast cell line from a patient with mast cell Leukemia. Leuk Res 12:345–355 Crivellato E, Ribatti D (2010) Mast cells: an evolutionary perspective. Biol Rev Camb Philos Soc 85:347–360 Grimbaldeston MA, Chen CC, Piliponski AM et al (2005) Mast cell-deficient W-sash c-kit mutant Kitw-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167:835–848

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Metcalfe DD, Baram D, Mekori YA (1997) Mast Cells. Physiol Rev 77:1033–1079 Ribatti D, Crivellato E (2009) The controversial role of mast cells in tumor growth. Int Rev Cell Mol Biol 275:89–131 Westerberg CM, Ekoff M, Nilsson G (2015) Regulation of mast cell survival and apoptosis. Methods Mol Biol 1220:257–267

Chapter 2

Mast Cell Ontogeny

2.1 Background Paul Ehrlich firstly described mast cells in his doctoral thesis at the Medical Faculty of Leipzig University (Crivellato et al. 2003). Ehrlich recognized two types of mast cells. The first, which could be identified and differentiated by its repertoire of coarse basophile granules (gamma granulation), lived in the connective tissues and apparently derived from them (tissue mast cells). The second, the counterpart of the neutrophil polymorph and eosinophil leukocyte, contained basophilic granulation of the fine type (delta granulation), its origin was in the bone marrow and its habitat was in the peripheral blood (blood mast cells, basophil or mast leukocyte). By the time that his textbook of 1898 came to be revised (Ehrlich 1898), the evidence for the myeloid origin of the blood mast cells was complete (Jolly 1900). After Ehrlich’s first description of mast cells, William Bate Hardy distinguished two types of granular basophil cells, i.e., the “coarsely granular basophile cells” and the “splanchnic basophile cells”, which both belonged to the population of “wandering cells” (the modern leukocytes) (Hardy and Wesbrook 1895; Kanthack and Hardy 1894). These cells corresponded to the subsets of connective tissue-type and mucosal mast cells, respectively, which would be described seventy years later by Enerbäck in rodents (Enerback 1966a, b). In 1967, Ginsburg and Lagunoff, first reported the development of mast cells in vitro and demonstrated that mast cells from lymph node cells of highly immunized mice, but not from bone marrow cells grew on fibroblast layers. In 1976, Ishizaka et al. confirmed mast cells growth by using a similar system, in long term culture of rat thymus cells on fibroblast layers, demonstrating the presence of Fc2RI on these cultured mast cells.

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2.2 First Evidence of Bone Marrow Origin The traditional view is that mast cells arise from mast cell committed precursors in the bone marrow, circulate as agranular cells, then traverse the vascular space and enter the tissues or serosal cavity, where they complete their development, giving rise to specific subsets of mast cells with characteristic profiles of intracellular mediators at distinct sites within the body. They reside close to blood vessels, nerves, and mucosal surfaces, such as respiratory tract and gastrointestinal tract. Mast cells are absent in avascular tissues, including mineral bone, cartilage and cornea (Crivellato et al. 2004). Mast cells originate from progenitor cells in the bone marrow, which move through the circulation and become mature mast cells after homing to different organs under the influence of the local microenvironment (Gurish and Austen 2001; Kitamura and Ito 2005). Mast cell progenitors enter the blood and exit into tissues by transendothelial migration. They have long been considered as undetectable in peripheral blood, but progress in flow cytometry resolution allowed reports on mast cell CD117+ and FcεRI+ found in the bloodstream of patients with systemic mastocytosis. Because the mouse genome is remarkably similar to that of humans, naturally occurring mast cell-deficient mice provide a useful tool for the identification of genes involved in functions of mast cells in humans. Nevertheless, the ability to generate non-transformed mast cells in vitro from wild-type (WT) and transgenic mice on different genetic backgrounds allowed detailed studies on the developmental control and functions of mast cells. In 1970s, the seminal work by Kitamura and colleagues demonstrated the reconstitution of mast cells in mast cell-deficient mice by the adaptive transfer of wild type bone marrow and indicated that these cells were of hematopoietic origin (Kitamura et al. 1977, 1978). These Authors demonstrated the virtual absence of mast cells in W/Wv mice. Kitamura’s findings that transplantation of bone marrow cells from the congenic +/+ mice or from beige mice, whose mast cells can be identified because of their giant cytoplasmic granules, repaired the mast cell deficiency of the W/Wv mice provided clear evidence that mast cells derived from precursors that reside in the bone marrow. Moreover, these works showed that mutations at W had a more profound effect on the mast cell than on any other hematopoietic lineage. In the early 1980s, mast cells were cultured from progenitors in mouse bone marrow using conditioned media (Nagao et al. 1981). In 1988, the first human mast cell line, HMC-1, was established from peripheral blood of a patient with mast cell leukemia (Butterfield et al. 1988). In humans, mast cells derive from CD34+ , CD13+ , CD117+ , FcεRI− , KIT+ committed pluripotent progenitors (Kirshenbaum et al. 1991), circulating as agranular mononuclear leukocytes, and complete their maturation into diverse peripheral tissues (Rodewald et al. 1996), where they acquire concomitant phenotypic diversity. Rodewald et al. (1996) provided one of the first phenotypic definitions of a committed mast cell progenitor and identified it in mouse foetal blood, defined by the surface phenotype Thy-1low KIThigh , lacked the expression of FcεRIα transcript and con-

2.2 First Evidence of Bone Marrow Origin

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tained cytoplasmic granules. Mast cell colony-forming cells reside within the bone marrow, spleen, peripheral blood, mesenteric lymph nodes and gut mucosa (Crapper and Schrader 1983). Mast cell progenitors, bearing the phenotype Lin− KIT+ Sca1− Ly6c− FcεRIα− CD27− β7+ T1/ST2+ , were identified in the adult bone marrow (Chen et al. 2005), developed into mast cells in culture and reconstitute mast cell compartment upon their transplantation into mast cell-deficient mice. A cell population (Lin− Kit+ FcγRII/IIIhi β7hi ) has been identified in the mouse spleen with the characteristics of a bi-potent progenitor for the basophil and mast cell lineages (Arinobu et al. 2005), termed basophil/mast cell common progenitor, and generated mainly from granulocyte/macrophage progenitors in the bone marrow. Specific arrays of differentiation factors such as stem cell factor (SCF) and interleukin-3 (IL-3) expressed by bone marrow stromal cells promote a distinctive pattern of mast cell-specific gene expression that includes genes encoding for distinct transcription factors (Winandy and Brown 2007). Balanced activity of transcription factors PU.1 and GATA is known to be required, along with the transcription factors MITF and possibly SCL, and the functions of GATA-2 and GATA-1 in this process can be distinguished (Arinobu et al. 2005; Babina et al. 2005; Nishiyama 2005). Mast cells can be derived from precursors separate from most myeloid lineages (Chen et al. 2005; Arinobu et al. 2005), and they develop through a pathway that excludes transcription factor C/EBP-α, which controls monocyte/dendritic cell programs (Iwasaki et al. 2006; Taghon et al. 2007). Increased GATA-2 or GATA-3 expression, provide direct access to the mast cell pathway for an uncommitted but differentiating lymphoid precursor (Taghon et al. 2007). Expression of FOG-1, a binding protein of GATA-1, during the progenitor period inhibits the differentiation of mast cells and redirects them into the erythroid, megakaryocytic, and granulocytic lineages (Cantor et al. 2008). GATA-3 is a crucial factor for mast cell development; its expression in the absence of Notch-DL1 signalling drives mast cell development (Taghon et al. 2007), and over-expression of GATA-3 in thymic progenitor cells promotes mast cell differentiation.

2.3 Development of Mast Cells Along the Myeloid Pathway Development of mast cells in mouse bone marrow occur along the myeloid pathway. The common myeloid progenitor (CMP) can give rise to either the magakaryocyteerythrocyte progenitor or to the granulocyte macrophage progenitor (GMP). The GMP can give rise to macrophages, eosinophils, neutrophils or to basophil-mast cell progenitor (BMCP). BMCP could be identified as a KIT+ , FCγ RII/RIII+ , β7 integrinhi , FCεRI− cell that only give rise to mast cells or basophils in culture and transfer of BMCP into mast cell deficient mice led to the appearance of mast cells in the spleen and peritoneal cavity (Arinobu et al. 2005). According to an alternative model of differentiation, a mast cell progenitor FCεRI− CD27− β7 integrin+ , IL33R+ was able to restore mast cell but not other lineages after transfer into mast cell deficient mice (Chen et al. 2005).

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2.4 Stem Cell Factor (Table 2.1) Stem cell factor (SCF) secreted by fibroblasts, stromal cells and endothelial cells is the most important cytokine involved in human and rodent mast cell development (Ashman 1999; Irani et al. 1992; Kirshenbaum et al. 1992; Mitsui et al. 1993; Valent et al. 1992), driving mast cell homing, proliferation and differentiation but also mast cell survival, migration and functional activation. C-kit is expressed on hematopoietic stem cells and is retained on mast cells throughout their development and differentiation but is down-regulated during differentiation of other bone marrow-derived cells, including basophils. In contrast to mast cells, basophils reach their maturation in bone marrow before their release into blood. SCF is the main survival and developmental factor for mast cells, is produced mainly by murine and human fibroblasts, as well as by several other cell types, where is expressed on the cell surface or released in soluble form (Williams et al. 1900). Injection of SCF into the skin of human being result in local accumulation of mast cells (Costa et al. 1996). Furitsu et al. (1989) found that monolayers of murine 3T3 fibroblasts or soluble factor derived from these cells could support human mast cell differentiation. These cells could be maintained in vitro for several months and had characteristics protease granule markers, tryptase and chymase (Irani et al. 1986). SCF is primarily responsible for mast cell growth in human cord blood or fetal liver/3T3 fibroblast co-culture system (Mitsui et al. 1993; Irani et al. 1992). The growth and differentiation of mast cells from unselected or CD34+ selected fetal liver or bone marrow cell populations is also controlled by SCF, although IL-3 play a supportive role (Valent et al. 1992; Kirshenbaum et al. 1989). Human mast cells grown in vitro from cord blood or fetal liver do not clearly proceed from tryptase containing mast cell (MCT/mucosal type) to tryptase-chymase containing mast cell (MCTC/serosal type) phenotypes; however, there appears to be a predominance of MCT cells in fetal liver and of MCTC in cord blood cultures. Differences in progenitor profiles of cord blood and fetal liver may predict in the presence of SCF, differences in mast cell phenotype commitment and differentiation in vitro (Valent et al. 1992). When bone marrow mast cells from normal mice were transferred to mast cell-deficient mice, the cells retained their mucosal cell phenotype at tissue sites that normal bear this phenotype while adopted a serosal mast cell phenotype at sites that contain such cells (Nakano et al. 1985). SCF normally reg-

Table 2.1 Effects of SCF in mast cell development and function

Mast cell survival Chemotaxis or haptotaxis of mast cells and their precursors Proliferation and differentiation of mast cells precursors Degranulation and secretion of mediators by mast cells

2.4 Stem Cell Factor (Table 2.1)

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ulates mast cell survival by repressing the levels of pro-apoptotic BH3-only protein Bim (Möller et al. 2005). Local treatment of mice with SCF can induce marked local increase in mast cell number, reflecting both enhanced recruitment/retention and/or maturation of mast cell precursors and proliferation of more mature mast cells (Tsai 1991). Lack of expression of a functional KIT receptor due to spontaneous mutation in both copies of Kit, as it occurs in genetically mast cell-deficient WBB6F1-Kit W -Kit W −v mice (W/W v mice), results in a virtual absence of tissue mast cells (Kitamura et al. 1978), reflected an abnormality intrinsic to the affected lineage (Kitamura et al. 1978), whereas the mast cell deficiency of Sl/Sld mice, which could not be corrected by bone marrow transplantation, reflected an abnormality in the microenvironment necessary for normal mast cell development (Kitamura and Go 1979). A Kit-mutant mouse has been characterized, the C57BL/6-Kit W −sh/W −sh mice (Grimbaldeston et al. 2005; Zhou et al. 2007), containing an inversion mutation of the transcriptional regulatory elements upstream of the Kit transcription start site on mouse chromosome 5 (Galli et al. 2005a, b). Mast cells develop in W/W v mice and in C57BL/6-Kit W −sh/W −sh mice if these mice receive bone marrow cells from normal littermates. Binding of SCF induces autophosphorylation of KIT and subsequent activation of several signalling molecules including PI3 K and mitogen-activated protein kinase (Lorenz 2002). Kit expression is upregulated in tumor cells and mutations of c-kit have been demonstrated in gastrointestinal stromal tumors and in various forms of mastocytosis and mast cell leukemia (Pittoni et al. 2011; Rubin et al. 2007; Valent et al. 2005). Prostate adenocarcinoma cells derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) failed to grow in mast cell deficient mice with mutations affecting c-kit, but grw normally in wild type controls (Pittoni et al. 2011). SCF is expressed by several tumors (Bellone et al. 2006; Huang et al. 2008; Zhang et al. 2000).

2.5 Integrins and Cell-Adhesion Molecules Human mast cell progenitors express the α4β1 integrin, which regulates their adhesion to activated endothelial cells (Boyce 2002). Mucosal mast cells possess β7 integrin, mediating the tissue specific homing of intestinal mast cell progenitors (Gurish et al. 2001). Using the β7 integrin null mice, Gurish et al. (2001) demonstrated a profound deficit in both mast cell progenitors and a deficit in the mature cells in the small intestine. In the mouse, large numbers of mast cell-committed precursors are constitutively recruited in the small intestine by a mechanism involving the α4β7 integrin (Gurish et al. 2001), expressed on the surface of mast cell precursors, binding to the “mucosal address in cell adhesion molecule-1” (MAdCAM-1) and to “vascular cell adhesion molecule-1” (VCAM-1) as endothelial counter-ligands for this integrin. Inflammation-induced recruitment of human mast cell progenitor to the lungs requires both α4β7 and α4β1, implicating organ-specific control of mast cell progenitor influx (Gurish et al. 2006). Dendritic cell expression of the transcription factor

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T-bet, which controls interferon (IFN)-γ production and Th1 cell differentiation from CD4+ T cells, regulates mast cell progenitor homing to mucosal tissue. Indeed, homing of mast cell progenitors to the lung or small intestine in T-bet(-/-) mice is reduced (Alcaide et al. 2007).

2.6 Chemokine Receptors and Interleukins Human mast cell precursors derived in vitro from cord blood express chemokine receptors including CXCR2, CCR3, CXCR4, and CCR5, and respond to the corresponding ligands in vitro (Ochi et al. 1999). Notch receptor-mediated signalling is involved in mast cell differentiation and homing, and Notch2 signalling in mast cells is required for proper localization of intestinal mast cells, and is critical for mast cell host-pathogen interface in the small intestine (Sakata-Yanagimoto et al. 2011). Directed migration by chemokine receptors and their ligands influence the localization of mast cell progenitors. CXCR-2 is critical for the constitutive localization of mast cell progenitors to the intestine (Abonia et al. 2005). IL-3 plays in rodents a fundamental role in mast cell development (Lantz et al. 1998), while the role of IL-3 on the development of human mast cells is controversial (Saito 2006). In 1983, Ihlejn and collaborators demonstrated that IL-3 promoted the growth of mast cells from mouse bone marrow. Rat mucosal mast cell phenotype in vitro is regulated by SCF interacting with c-kit while IL-3 may enhance phenotype switch into a serosal mast cell (Tei et al. 1994). IL-3 is not required for the development of human cord-blood derived mast cells in the presence of low oxygen concentration (Kinoshita et al. 1999). However, IL-3 can enhance SCF-dependent mast cell development at low cell densities at normal oxygen concentration (Saito 2006). Nerve growth factor (NGF) promotes differentiation and proliferation of mouse bone marrow mast cells in the presence of IL-3 (Matsuda et al. 1991). A mast cell committed precursor characterized by a THY1low KIThi mMCP2 (mast cell protease-2, also known as MCPT2)+ mMCP4 (also known as MCP4)+ CPA3+ phenotype was identified in the fetal blood at day 15.5 of gestation (Rodewald et al. 1996). These cells gave rise to pure colonies of mast cells upon culturing with IL-3 and SCF. Intravenous adaptive transfer of these cells into W/Wv mice reconstituted the mast cell population in the peritoneal cavity of the host, providing the proof that mast cell precursors traffic to the tissue and differentiate. Levi-Schaffer, Austen, and co-workers demonstrated that fibroblasts supported development of IL-3-dependently cultured mast cells in the mature connective-type mast cells, and that mature human lung mast cells were maintained in vitro when co-cultured with fibroblasts (Levi-Schaffer et al. 1986, 1987a, b). Accordingly, in 1989, Furitsu et al. demonstrated the development of human mature mast cells from hematopoietic cells when co-cultured with monolayers of mouse 3T3 fibroblasts, or soluble factors derived from these cells. The identity of this factor has revealed as SCF or c-kit ligand (Irani et al. 1992; Mitsui et al. 1993; Valent et al. 1992).

2.6 Chemokine Receptors and Interleukins

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Other cytokines and growth factors which regulate mast cell development and differentiation include IL-4, IL-9, IL-10, transforming growth factor beta (TGFβ) and NGF (Okayama and Kawakami 2006). IL-4 acts synergistically with SCF in the control of mast cell survival, proliferation as well as IgE-dependent mediator release (Bischoff et al. 1999). IL-4 priming of human mast cells for enhanced proliferation and mediator release is associated with an increased activity of extracellular signal-regulated kinase (ERK) and c-Fos (Lorentz and Bischoff 2001). IL-4 reduces pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and IL-6 and in turn enhancing Th2 cytokines such as IL-5 and IL-13 (Lorentz and Bischoff 2001). Mouse bone marrow-derived mast cells (BMMCs) undergo phenotypic changes in the presence of IL-9 in combination with SCF that consist in the acquisition of a mucosal mast cell phenotype(Okayama and Kawakami 2006). In humans, IL-9 and IL-5 stimulate SCF-mediated proliferation of mast cells from cord blood cells, bone marrow and peripheral cells (Matsuzawa et al. 2003). IL-10 in combination with IL-3 or IL-4, IL-10 enhances mast cell growth. The first evidence that mast cells are receptive to NGF showed that exogenous administration of highly purified NGF into newborn rats induces a marked increase in the number and size of mast cells in peripheral tissues (Aloe and Levi-Montalcini, 1977). NGF promotes proliferation and differentiation of mouse BMMCs in the presence of IL-3 (Matsuda et al. 1991), while NGF in combination with SCF synergistically suppresses human mast cell apoptosis (Kanbe et al. 2000). Moreover, NGF acts via tyrosine kinase receptors (TrkA, B, C), different from the c-kit activated by SCF (Tam et al. 1997). Human mast cells express mRNA and protein for the Tkr ligands NGF, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (Tam et al. 1997). Neurotrophin-3, in turn, promotes maturation of human intestinal mast cells (Lorentz et al. 2007).

References Abonia JP, Austen KF, Rollins BJ et al (2005) Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR45. Blood 105:4308–4313 Alcaide P, Jones TG, Lord GM et al (2007) Dendritic cell expression of the transcription factor t-bet regulates mast cell progenitor homing to mucosal tissue. J Exp Med 204:431–439 Aloe L, Levi Montalcini R (1977) Mast cells increase in tissues of neonatal rats injected with the nerve growth factor. Brain Res 133:358–366 Arinobu Y, Iwasaki H, Gurish MF et al (2005) Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl Acad Sci USA 102:18105–18110 Ashman LK (1999) The biology of stem cell factor and its receptor C-Kit. Int J Biochem Cell Biol 31:1037–1051 Babina M, SchülkeY Kirchhof L et al (2005) The transcription factor profile of human mast cells in comparison with monocytes and granulocytes. Cell Mol Life Sci 62:214–226 Bellone G, Smime C, Carbone A et al (2006) KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and oucomes. Int J Oncol 29:851–859 Bischoff SC, Sellge G, Lorentz A et al (1999) IL-4 enhances proliferation and mediator release in mature human mast cells. Proc Natl Acad Sci 96:8080–8085

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Boyce JA (2002) Human mast cell progenitors use alpha 4-integrin, VCAM-1, and PSGL-1 Eselectin for adhesive interactions with human vascular endothelium under flow conditions. Blood 99:2890–2896 Butterfield JH, Weiler D, Dewald G et al (1988) Establishment of an Immature Mast Cell Line from a Patient with Mast Cell Leukemia. Leuk Res 12:345–355 Cantor AB, Iwasaki H, Arinobu Y et al (2008) Antagonism of FOG-1 and GATA factors in fate choice for the mast cell lineage. J Exp Med 205:611–624 Chen CC, Grimbaldeston MA, Tsai M et al (2005) Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci USA 102: 11408–11413. Costa JJ, Demetri GD, Harrist TJ et al (1996) Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J Exp Med 183:2681–2686 Crapper RM, Schrader JW (1983) Frequency of mast cell precursors in normal tissues determined by an in vitro assay: antigen induces parallel increases in the frequency of P cell precursors and mast cells. J Immunol 131:923–928 Crivellato E, Beltrami C, Mallardi F et al (2003) Paul Ehrlich’s doctoral thesis: a milestone in the study of mast cells. Br J Haematol 123:19–21 Crivellato E, Nico B, Battistig M et al (2004) The thymus is a site of mast cell development in chicken embryos. Anat Embryol (Berl) 209:243–249 Ehrlich PLA (1898) Die Anemie, 1. Holder, Normale und Patologische Histologie des Blutes Wien Enerbäck L (1966a) Mast cells in rat gastrointestinal mucosa. I. effects of fixation. Acta Pathol Microbiol Scand 66:289–302 Enerbäck L (1966b) Mast cells in rat gastrointestinal mucosa. 2. dye-binding and metachromatic properties. Acta Pathol Microbiol Scand 66:303–312 Furitsu T, Saito H, Dvorak AM et al (1989) Development of human mast cells in vitro. Proc Natl Acad Sci 86:10039–10043 Galli SJ, Kalesnikoff J, Grimbaldeston MA et al (2005a) Mast cells as “Tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 23:749–786 Galli SJ, Nakae S, Tsai M (2005b) Mast cells in the development of adaptive immune responses. Nat Immunol 6:135–142 Ginsburg H, Lagunoff D (1967) The in vitro differentiation of mast cells. Cultures of cells from immunized mouse lymph nodes and thoracic duct lymph on fibroblast monolayers. J Cell Biol 35:685–697 Grimbaldeston MA, Chen CC, Piliponski AM et al (2005) Mast cell-deficient W-sash C-kit mutant kitw-Sh/W-Sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167:835–848 Gurish MF, Austen KF (2001) The diverse role of mast cells. J Exp Med 194:F1–F5 Gurish MF, Boyce JA (2006) Mast cells: ontogeny, homing, and recruitment of a unique innate effector cell. J Allergy Clin Immunol 117:1285–1291 Gurish MF, Tao H, Abonia JP et al (2001) Intestinal mast cell progenitors require CD49dbeta7 (Alpha4beta7 Integrin) for tissue-specific homing. J Exp Med 194:1243–1252 Hardy WB, Wesbrook FF (1895) The wandering cells of the alimentary canal. J Physiol 18:490–493 Huang B, Lei Z, Zhang GM et al (2008) SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood 112:1269–1279 Irani AA, Schechter NM, Craig SS et al (1986) Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA 83:4464–4468 Irani AM, Nilsson G, Miettinen U et al (1992) Recombinant human stem cell factor stimulates differentiation of mast cells from dispersed human fetal liver cells. Blood 80:3009–3021 Ishizaka T, Okudaira H, Mauser LE et al (1976) Development of rat mast cells in vitro. I. Differentiation of mast cells from thymus cells. J Immunol 116:747–754 Iwasaki H, Mizuno SI, Arinobu Y et al (2006) The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev 20:3010–3021 Jolly M (1900) Clasmatocytes et mastzellen. Comp Rend Soc Biol (Paris) 52:437–455

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Kanbe N, Kurosawa M, Miyachi Y et al (2000) Nerve growth factor prevents apoptosis of cord blood-derived human cultured mast cells synergistically with stem cell factor. Clin Exp Allergy 30:1113–1120 Kanthack AA, Hardy WB (1894) The morphology and distribution of the wandering cells of mammalia. J Physiol 17:80–119 Kinoshita T, Sawai N, Hidaka E et al (1999) Interleukin-6 directly modulates stem cell factordependent development of human mast cells derived from CD34 + cord blood cells. Blood 4:496–508 Kirshenbaum AS, Kessler SW, Goff JP et al (1991) Demonstration of the origin of human mast cells from CD34 + bone marrow progenitor cells. J Immunol 146:1410–1415 Kirshenbaum AS, Goff JP, Dreskin SC et al (1989) IL-3-dependent growth of basophil-like cells and mast like cells from human bone marrow. J Immunol 149:2424–2429 Kirshenbaum AS, Goff JP, Kessler SW et al (1992) Effect of IL-3 and stem cell factor on the appearance of human basophils and mast cells from CD34 + pluripotent progenitor cells. J Immunol 148:772–777 Kitamura Y, Go S (1979) Decreased production of mast cells in S1/S1d anemic mice. Blood 53:492–497 Kitamura Y, Ito A (2005) Mast cell-committed progenitors. Proc Natl Acad Sci 102:11129–11130 Kitamura Y, Shimada M, Hatanaka et al (1977) Development of mast cells from grafted bone marrow cells in irradiated mice. Nature 268: 442–443 Kitamura Y, Go S, Hatanaka K (1978) Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 52:447–452 Lantz CS, Boesiger J, Song CH et al (1998) Role for interleukin-3 In mast-cell and basophil development and in immunity to parasites. Nature 392:90–93 Levi-Schaffer F, Austen KF, Gravallese PM et al (1986) Coculture of Interleukin 3-dependent mouse mast cells with fibroblasts results in a phenotypic change of the mast cells. Proc Natl Acad Sci 83:6485–6488 Levi-Schaffer F, Austen KF, Caulfield JP et al (1987a) Co-culture of human lung-derived mast cells with mouse 3T3 fibroblasts: morphology and Ige-mediated release of histamine, prostaglandin D2, and leukotrienes. J Immunol 139:494–500 Levi-Schaffer F, Dayton ET, Austen KF et al (1987b) Mouse bone marrow-derived mast cells cocultured with fibroblasts. morphology and stimulation-induced release of histamine, leukotriene B4, leukotriene C4, and prostaglandin D2. J Immunol 139:3431–3441 Lorentz A (2002) Regulatory effects of stem cell factor and interleukin-4 on adhesion of human mast cells to extracellular matrix proteins. Blood 99:966–972 Lorentz A, Bischoff SC (2001) Regulation of human intestinal mast cells by stem cell factor and IL-4. Immunol Rev 179:57–60 Lorentz A, Hoppe J, Worthmann H et al (2007) Neurotrophin-3, but not nerve growth factor, promotes survival of human intestinal mast cells. Neurogastroenterol Motil 19:301–308 Matsuda H, Kannan Y, Ushio H et al (1991) Nerve growth factor induces development of connective tissue-type mast cells in vitro from murine bone marrow cells. J Exp Med 174:7–14 Matsuzawa S, Sakashita K, Kinoshita T et al (2003) IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J Immunol 170:3461–3467 Mitsui H, Furitsu T, Dvorak AM et al (1993) Development of human mast cells from umbilical cord blood cells by recombinant human and murine c-kit ligand. Proc Natl Acad Sci 90:735–739 Moller C, Alfredsson J, Engström M et al (2005) Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim. Blood 106:1330–1336 Nagao K, Yokoro K, Aaronson S (1981) Continuous lines of basophil/mast cells derived from normal mouse bone marrow. Science 212:333–335

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Nakano T, Sonoda T, Hayashi C, et al (1985) Fate of bone marrow-derived cultured mast cells after intracutaneous, intraperitoneal, and intravenous transfer into genetically mast cell-deficient W/Wv mice: evidence that cultured mast cells can give rise to both connective tissue type and mucosal mast cells. J Exp Med 162:1025–1043 Nishiyama C (2005) GATA-1 Is Required for Expression of Fc RI on Mast Cells: Analysis of Mast Cells Derived from GATA-1 Knockdown Mouse Bone Marrow. Int Immunol 17:847–856 Ochi H, Hirani WM, Yuan Q et al (1999) T helper cell type 2 cytokine-mediated comitogenic responses and Ccr3 expression during differentiation of human mast cells in vitro. J Exp Med 190:267–280 Okayama Y, Kawakami T (2006) Development, migration and survival of mast cells. Immunol Res 34:97–115 Pittoni P, Tripodo C, Piconese S et al (2011) Mast cell targeting hampers prostate adenocarcinoma development but promotes the occurrence of highly malignant neuroendocrine cancers. Cancer Res 71:5987–5997 Rodewald HR, Dessing M, Dvorak AM et al (1996) Identification of a committed precursor for the mast cell lineage. Science 271:818–822 Rubin BP, Heinrich MC, Corless CL (2007) Gastrointestinal stromal tumour. Lancet 369:1731–1734 Saito H (2006) Culture of human mast cells from hemopoietic progenitors. Methods Mol Biol 315:113–122 Sakata-Yanagimoto M, Sakai T, Miyake Y et al (2011) Notch 2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine. Blood 117:128–134 Taghon T, Yui MA, Rothenberg EV (2007) Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3. Nat Immunol 8:845–855 Tam SY, Tsai M, Yamaguchi M et al (1997) Expression of functional trka receptor tyrosine kinase in the HMC-1 human mast cell line and in human mast cells. Blood 90:1807–1820 Tei H, Kasugai T, Tsuijimura T et al (1994) Characterization of cultured mast cells derived from Ws/Ws mast cell-deficient rats with a small deletion at tyrosine kinase domain of c-kit. Blood 83:913–925 Tsai M (1991) The rat c-kit ligand, stem cell factor, induces the development of connective tissuetype and mucosal mast cells in vivo. analysis by anatomical distribution, histochemistry, and protease phenotype. J Exp Med 174:125–131 Valent P, Spanblochl E, Sperr WR et al (1992) Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood 80:2237–2245 Valent P, Akin C, Sperr WR et al (2005) Mastocytosis: pathology, genetics and current options for therapy. Leuk Lymph 46:35–48 Williams HU (1900) A critical summary of recent literature on plasma-cells and mast cells. Am J Med Sci 119:702–709 Winandy S, Brown M (2007) No DL1 notch ligand? GATA Be a mast cell. Nat Immunol 8:796–797 Zhang W, Stoica G, Tasca SI et al (2000) Modulation of tumor angiogenesis by stem cell factor. Cancer Res 60:6757–6762 Zhou JS, Xing W, Friend DS et al (2007) Mast cell deficiency in Kit(W-Sh) mice does not impair antibody-mediated arthritis. J Exp Med 204:2797–2802

Chapter 3

The Staining of Mast Cells

3.1 Background The histochemical techniques for subdividing mast cells stemmed from the observation by Ehrlich’ in 1876 that their lysosomal granules have the capacity to take up and stain metachromatically with basic dyes, such as toluidine blue. Among the histochemical methods to stain mast cells, it is to note to mention Sudan Black B, Luna stain or even Ziehl-Neelsen, which has been assessed historically (Rest and Lee 1979). In 1999, Cannas-Simões and Schonning, evaluated 18 methods for staining mast cells in dogs. Enerback demonstrated in 1986 that rodent mast cells subpopulations could be differentially stained with Alcian blue and berberine sulfate. Moreover, Enerback showed that mast cells from mucosal surfaces were sensitive to formaldehyde fixation in that they failed to stain metachromatically on additional exposure to dyes, whereas mast cells from connective tissues were insensitive to formaldehyde fixation. Before the introduction of monoclonal antibodies against proteases, mast cells were stained by metachromatic stains, such as toluidine blue and Alcian blue.

3.2 Metachromasia Mast cell granules can naturally induce metachromatic staining. Metachromatic stains include Romanowsky methods (Wright’s, Giemsa, May-Grunwald Giemsa, Leishman’s), toluidine blue, and others. Toluidine blue first emerged in 1856, courtesy of a British chemist called William H. Perkin. Although he was working on the synthesis of quinine, Perkin instead produced a blue substance with good dyeing properties. Initially it became known as aniline purple. Being mostly used in the dye industry, this was the first synthetic organic chemical dye. Later it became known as toluidine blue, and began being used

© Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_3

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for medical purposes, in particular as a histological special stain to highlight certain components. Paul Ehrlich described in his doctoral dissertation a class of aniline-positive cells of the connective tissues endowed with cytoplasmic metachromatic granules for which he coined the name of “Mastzellen”. The first use of the term “metachromatic” was due to Ackroyd in 1876 to indicate that the structure being dyed assumed a color different from that of the dye itself. In 1879, Ehrlich used for the first time the word in a biologic context to described the staining reactions of blood leukocytes on the basis of their specific affinities for various dyes (Ehrlich 1879, 1894, 1898). He encountered cells with basophilic, metachromatic granules, and thus came to recognize two types of mast cells. The first, which could be identified and differentiated by its repertoire of coarse basophile granules (gamma granulation), lived in the connective tissues and apparently derived from them (tissue mast cells). The second, the counterpart of the neutrophil polymorph and eosinophil leukocyte, contained basophilic granulation of the fine type (delta granulation), its origin was in the bone marrow and its habitat was in the peripheral blood (blood mast cells, basophil). In 1937, Scandinavian researchers provided fundamental new insight as to mast cell structural profile. The mast cell component prophesized by Ehrlich as the responsible agent for granule metachromasia was revealed (Holmgren 1937; Jorpes and Wilander 1937). Following Jorpes’ discovery that the anticoagulant heparin was subject to stain metachromatically with toluidine blue, Holmgren and Wilander reconsidered Ehrlich’s observation that mast cell granules stained metachromatically with toluidine blue. These authors were able to set a correlation between the number of toluidine blue-positive mast cell in various tissues and their heparin content. Metachromatic staining is important in the detection of mast cells and is strongly recommended as routine stain for mast cells. One of the most frequently metachromatic stains is toluidine blue which stain mast cell granules purple to red (Fig. 3.1). Dilute staining solutions should be used in order to demonstrate strongly metachromatic elements (Kramer and Windrum 1955). The pH of the dye solution used is important. Lennert (1962) have shown that the use of a series of toluidine blue solutions at pH levels varying from 2.62 to 7.00 might help differentiate benign from malignant cases of human mastocytosis. This issue was further developed afterwards since it was shown that benign lesions stained with toluidine blue at lower pH, whereas malignant lesions were poorly stained at pH < 3.5 (Klatt et al. 1983). Metachromasia is due to the presence of tissue polyanions that induce a polymerization of dye molecules. A distance of around 0.5 nm between negatively charged groups is needed to induce such polymerization (D’mello et al. 2016). It involves a shift in the absorption spectrum of the dye towards shorter wave-lengths and is accompanied by a hypochrome color changes of the dye from blue towards violet, red or orange. Metachromasia of anionic tissue can be demonstrated with many cationic dyes such as thiazines, oxamines, azines, and xanthenes, and with fluorescent dyes such as Acridine orange. The thiazine dyes Toluidine blue and Azure A are by far the most widely used. Metachromasia is best observed in water solution of low ionic strength. A large number of anionic tissue sites are metachromatic under such conditions (Spicer and Leppy 1967).

3.2 Metachromasia

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Fig. 3.1 Semithin section of rat peritoneal mast cells stained with toluidine blue. Numerous cytoplasmic metachromatic granules are recognizable (Reproduced from Ribatti et al. 2001a, b)

Mast cells are round shaped in the proximity of blood vessels, whereas they displayed an elongated shape in the interstitial regions. In addition, mast cell often showed reduced numbers of granules and disorganized granule content, suggesting an ongoing degranulation process. The analysis at higher magnifications allowed the identification of degranulating mast cells, characterized by numerous extracellular metachromatic granules and/or by a poor intracytoplasmic granule content, and nondegranulating mast cells without any granule in the close extracellular space.

3.3 Alcian Blue-Safranin Strongly metachromatic polyanions such as the sulfated glycosaminoglycans (GAGs) of mast cell granules retain a red or violet metachromasia after dehydration in ethanol and mounting in synthetic resins. Two copper phthalocyanin dyes are of special interest for the staining of mast cells, Alcian blue 8GX and Astrablau 6GLL. Alcian blue, formulated by Scott et al. (1964) is more easily available and better specified and should therefore be preferred. Alcian blue interacts with polyanions such as heparin in aqueous solutions to give insoluble precipitates in which the two components are bound by ionic linkages. Connective tissue mast cells of rats and mice have low affinity for Alcian blue. Mast cells in cervical lymph nodes and uterus stained strongly with Alcian blue at pH 2.5 (Spicer 1963). In the 1960s, Enerbäck, based on their specific staining characteristics and preferential tissue homing, described two morphologically distinct subpopulations of rodent mast cells, named connective tissue mast cells (CTMCs), located the mucosae of the respiratory and gastrointestinal tracts, and serosae and mucosal mast cells (MMCs), present to the connective tissues (Enerback 1966a, b, 1986). CTMCs could be distinguished from MMCs by staining in red with safranin due to the presence of large amounts of heparin in their secretory granules. In the mouse, indeed, the proteoglycan content of mast cell granules varied in the different mast cell subtypes. CTMCs contained heparin that lacked in MMCs. Conversely, MMCs expressed chondroitin sulphates A and B, which were not found in CTMCs, whereas both mast

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cell subtypes stored chondroitin sulphate E in their granules. Thus, in contrast to CTMCs, MMCs were sensitive to routine formalin fixation and could not be identified in standard histological sections. CTMCs can be demonstrated after fixation with 10% neutral buffered formalin, while MMCs require fixation in non-aldehyde solutions such as Carnoy’s (Irani and Schwartz 1989). After appropriate fixation and sequential staining with Alcian blue and safranin, the MMCs stained blue, being thus differentiated from CTMCs which stained with safranin and were red. Differential affinity for Alcian blue can be visualized with a sequential staining of Alcian blue followed by Safranin (Spicer 1960). Immature embryonic mast cells contain granules which stain with Alcian blue rather than Safranin. With the Alcian blue-Safranin sequence maturation of mast cells is accompanied by a change in the staining properties from blue to red (Combs 1965).

3.4 The Tyrosine Kinase Kit Receptor Mast cells, but not basophils, express the kit receptor for SCF (Fig. 3.2), which not only drive terminal differentiation of mast cells but has also other important roles in regulating mast cell biology, such as survival, activation and degranulation of mature mast cells. In the immunohistochemical staining, the c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor, c-kit (CD117), which is closely related to the platelet derived growth factor (PDGF) family. This antibody recognizes the extracellular domain and is expressed by a variety of normal and abnormal cell types. In normal cells, the CD117 antibody has been shown to label breast epithelium, germ cells, melanocytes, stem cells, mast cells, salivary glands, esophagus, cerebellum,

Fig. 3.2 Predominantly focal paranuclear c-kit protein expression in mast cells of a canine mast cell tumor. Immunohistochemistry is performed with primary anti-c-kitR antibody. Single arrows indicate focal brown paranuclear immunostaining, while double arrows indicate a vessel (Reproduced from Patruno et al. 2014)

3.4 The Tyrosine Kinase Kit Receptor

19

hippocampus, and spinal cord (Lammie et al. 1994). In mast cells the marking is at the level of the plasma membrane, while in other cells is at the level of cytoplasm. Furthermore, a large part of mast cells, including those of the colon, stomach, lung, uterus and bladder, do not stain with c-kit (Qi et al. 2003). Because CD117 is also expressed on immature hematopoietic progenitor cells, additional markers should be applied to define the mast cell component by flow cytometry in bone marrow samples. To distinguish CD117-positive mast cells from CD117-non hematopoietic cells, staining of mast cells with a monoclonal antibody against CD 45 is recommended (Escribano et al. 2001).

3.5 Tryptase and Chymase Mast cell proteases represent major protein components of secretory granules, representing up to 50% of the total protein content of the granule, but the role of each individual protease in mast cells remains poorly understood. The proteases are classified into a carboxypeptidase, chymases, and tryptases. Tryptase has been considered a discriminating marker for mast cells. As tryptase is an abundant secretory product of mast cells and is restricted almost entirely to this cell type, its measurement in biological fluids can provide compelling evidence for mast cell activation. The measurement of tryptase in serum or plasma has proved helpful as a diagnostic aid in cases of systemic anaphylaxis and in mastocytosis (Scwartz et al. 1987, 1995). Mast cells differ in their protease expression pattern depending on the tissue location where they reside. By 1960, two proteases with chymotrypsin- and trypsin-like activity were identified in mast cells (Benditt and Arase 1959; Benditt 1956; Glenner and Cohen 1960), and enzyme activity was recognized to localize within intracellular granules. The enzymes were purified in the 1980s and renamed tryptase and chymase (Schechter et al. 1986; Schwartz et al. 1981). Mast cells from different anatomical sites contained different profiles of these enzymes as well as of other proteases (Figs. 3.3 and 3.4). Human mast cells were divided into two subtypes depending on the expression of different proteases in their granules (Irani et al. 1986). Mast cells, which contained tryptase only, were designated as MCsT or “immune cell-associated” mast cells predominantly located in the respiratory and intestinal mucosa, where they co-localized with T lymphocytes. Mast cells that contained both tryptase and chymase, along with other proteases such as carboxypeptidase A and cathepsin G (Fig. 3.5), were referred to as MCsTC , and were predominantly found in connective tissue areas, such as skin, submucosa of stomach and intestine, breast parenchyma, myocardium, lymph nodes, conjunctiva and synovium. A third type of mast cell, called MCC expressing chymase without tryptase and resided mainly in the submucosa and mucosa of the stomach, small intestinal submucosa and colonic mucosa (Irani and Schwartz 1994). Interestingly, human MCsT were seen to correspond most closely to rodent MMCs, whereas MCsTC resembled rodent CTMCs.

20

3 The Staining of Mast Cells

Fig. 3.3 An elongated mast cell stained with an anti-tryptase antibody (Reproduced from Ribatti and Crivellato 2014)

Fig. 3.4 Immnohistochemical staining for CD31, tryptase and chymase in stage II (a–c) and stage IV (d–f) human gastric cancer. In a, d endothelial cells immunoreactive for CD31; in b, e tryptasepositive mast cells; in c, f chymase-positive mast cells. Blood vessels and mast cells are distributed around the gastric glands. The number of blood vessels and mast cells is higher in stage IV as compared to stage II bioptic specimens and chymase-positive are lower as compared to tryptasepositive mast cells (Reproduced from Ribatti et al. 2010)

3.6 Other Stainings

21

Fig. 3.5 Dual immunofluorescence for tryptase (red, in a) and cathepsin-G (green, in b) and for both proteins (orange, in c) in a biopsy specimen of human cutaneous mastocytosis (Reproduced from Ribatti et al. 2009)

3.6 Other Stainings Chloroacetate-esterase is found in mast cells. Specimens are incubated with naphthol AS-D chloroacetate in the presence of freshly formed diazonium salt. Enzymatic hydrolysis of ester linkages liberates free naphthol compounds which couple with diazonium salt forming highly colored deposits at the site of enzyme activity (Moloney et al. 1960). Unlike most enzyme stains, the chloroacetate esterase can be done on fixed, paraffin embedded tissue. The slides are incubated in a solution containing the substrate naphthol AS-D chloroacetate. Then the esterase contained in the neutrophils and mast cells binds with the chloroacetate. This latter releases the naphthol group, which binds to the diazonium dye pararosanalin (basic fuchsin), another component of the incubating solution. Pararosanilin or basic fuchsin gives a deep pink-red color to the granules, while hematoxylin counterstains the nuclei blue. Berberine forms a strongly fluorescent complex with heparin proportional to heparin content in mast cell granules (Enerback 1974), allowing quantitation of heparin both by microscope fluorometry and by flow cytometry (Enerback 1974). Berberine staining may be used also for visualization of mast cells in tissue sections (Dimlich et al. 1980). Mast cell stain intensely at pH 8.00–10.5 with the anionic bis-azo dye Biebrich scarlet (Spicer 1963) and stain strongly with naphtol AS chloroacetate as a substrate and diazo-coupling fixation in acetone or neutral formalin (Gomori 1953). Histamine can be demonstrated histochemical with a fluorescent reaction with o-phthalaldeyde (OPT) (Shelley et al. 1968; Juhlin and Shelley 1966).

22

3 The Staining of Mast Cells

References Ackroyd W (1876) Metachronism or Colour Change. Chem News 33:60 Benditt EP (1956) An enzyme in mast cells with some properties resembling chymotrypsin. Fed Proc 1956(15):507 Benditt EP, Arase M (1959) An enzyme in mast cells with properties like chymotrypsin. J Exp Med 110:451–460 Combs JW (1965) Differentiation and proliferation of embryonic mast cells of the rat. J Cell Biol 25:577–592 D’mello AXP, Sylvester TV, Ramya V et al (2016) Metachromasia and Metachromatic dyes: a review. Int J Adv Health Sci 2:12–17 Dimlich RV, Meineke HA, Reilly FD et al (1980) The fluorescent staining of heparin in mast cells using berberine sulfate: compatibility with paraformaldehyde or o-phthalaldehyde induced fluorescence and metachromasia. Stain Technol 55:217–223 Ehrlich P (1879) Beiträge zur Kenntnis der Granulierten Bindegewebszellen und der Eosinophilen Leukozyten. Arch Anat Physiol 3:166–169 Ehrlich P (1894) Farbenanalytisehe Untersuchungen zur Histologie und Klinik Des Blutes. DMW—Dtsch med Wochenschr 20:135–136 Ehrlich PLA (1898) Die Anemie, 1. Normale und Patologische Histologie des Blutes Wien: Holder Enerbäck L (1966a) Mast cells in rat gastrointestinal Mucosa. I. Effects of fixation. Acta Pathol Microbiol Scand 66:289–302 Enerbäck L (1966b) Mast cells in rat gastrointestinal Mucosa. 2. Dye-binding and metachromatic properties. Acta Pathol Microbiol Scand 66:303–312 Enerbäck L (1974) Berberine sulphate binding to mast cell polyanions: a cytofluorometric method for the quantitation of heparin. Histochemistry 42:301–313 Enerbäck L (1986) Mast cell heterogeneity: the evolution of the concept of a specific mucosal mast cell. In: Befus AD, Bienenstock J, Denburg JA (eds) Mast cell differentiation and heterogeneity. Raven Press, New York, pp 1–26 Escribano L, D´ıaz-Agust´ın B, Bellas C et al (2001) Utility of flow cytometric analysis of mast cells in the diagnosis and classification of adult mastocytosis. Leuk Res 25:563–70 Glenner GG, Cohen LA (1960) Histochemical demonstration of a species-specific trypsin-like enzyme in mast cells. Nature 185:846–847 Gomori G (1953) Chloroacyl esters as histochemical substrates. J Histochem Cytochem 1:469–470 Holmgren HWO (1937) Beitrag zur Kenntnis der Chemie und Funktion der Ehrlichschen Mastzellen. Z Mikrosk Anat Forsch 42:242–278 Irani AM, Schwartz LB (1989) Mast cell heterogeneity. Clin Exp Allergy 19:143–155 Irani AM, Schwartz LB (1994) Human mast cell heterogeneity. Allergy Proc 15:303–308 Irani AA, Schechter NM, Craig SS et al (1986) Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA 83:4464–4468 Jorpes EHH, Wilander O (1937) Über das Vorkommen von Heparin in den Gefässwänden und in den Augen. Ein Beitrag zur Physiologie der Ehrlichschen Mastzellen. Z Mikrosk Anat Forsch 42:279–301 Juhlin L, Shelley WB (1966) Detection of histamine by a new fluorescent o-phthalaldehyde stain. J Histochem Cytochem 14:525–528 Klatt EC, Lujes RJ, Meyer PR (1983) Benign and malignant mast cell proliferations. Diagnosis and separation using a Ph-dependent toluidine blue staining in tissue section. Cancer 51:1119–1124 Kramer H, Windrum GM (1955) the metachromatic staining reaction. J Histochem Cytochem 3:227–237 Lammie A, Dobnojak M, Gerald W et al (1994) Expression of C-Kit and kit ligand proteins in normal human tissues. J Histochem Cytochem 42:1417–1425 Lennert K (1962) Zur pathologischen Anatomie von Urticaria pigmentosa und Mastzellenreticulose. Klin Wochenschr 40:61–67

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Moloney WC, McPherson K, Fliegelman L (1960) Esterase activity in leukocytes demonstrated by the use of naphthol as-D chloroacetate substrate. J Histochemi Cytochemi 8:200–207 Patruno R, Marech I, Zizzo N et al (2014) c-kit expression, angiogenesis, and grading in canine mast cell tumour: a unique model to study c-kit driven human malignancies. Biomed Res Int 2014:730246 Qi JC, Li L, Li Y et al (2003) An antibody raised against in vitro-derived human mast cells identifies mature mast cells and a population of cells that are Fc epsilon Ri (+), tryptase (−), and chymase (−) in a variety of human tissues. J Histochem Cytochem 51:643–653 Rest JR, Lee RL (1979) staining of mast cell granules by the ziehl-neelsen method and differential diagnosis of malignant dermal tumours in the dog. Vet Rec 104:79 Ribatti D, Crivellato E (2014) Mast cell ontogeny: an historical overview. Immunol Lett 159:11–14 Ribatti D, Crivellato E, Candussio L et al (2001a) Mast cells and their secretory granules are angiogenic in the chick embryo chorioallantoic membrane. Clin Exp Allergy 31:602–608 Ribatti D, Vacca A, Nico B et al (2001b) The role of mast cells in tumour angiogenesis. Brit J Haematol 115:514–521 Ribatti D, Nico B, Finato N et al (2009) Co-localization of tryptase and cathepsin-G in mast cells in cutaneous mastocytosis. Cancer Lett 279:209–212 Ribatti D, Guidolin D, Marzullo A et al (2010) Mast cells and angiogenesis in gastric carcinoma. Int J Exp Pathol 91:350–356 Schechter NM, Choi JK, Slavin DA et al (1986) Identification of a chymotrypsin-like proteinase in human mast cells. J Immunol 137:962–970 Schwartz LB, Lewis RA, Austen KF (1981) Tryptase from human pulmonary mast cells. Purification and characterization. J Biol Chem 256:11939–11943 Schwartz LB, Irani AA, Roller K et al (1987) quantitation of histamine, tryptase and chymase in dispersed human T and TC mast cells. J Immunol 138:2611–2615 Schwartz LB, Sakai K, Bradford TR et al (1995) The alpha form of human tryptase is the predominant form present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest 96:2702–2710 Scott JE, Quintarelli G, Dellovo MC (1964) The chemical and histochemical properties of alcian blue. Histochemie 4:73–85 Shelley WB, ÖHman S, Parnes HM (1968) Mast cell stain for histamine in freeze-dried embedded tissue. J Histochem Cytochem 16:433–439 Spicer SS (1960) A correlative study of the histochemical properties of rodent acid mucopolysaccharides. J Histochem Cytochem 8:18–35 Spicer SS (1963) Histochemical properties of mucopolysaccharixe and basic protein in mast cells. Ann N Y Acad Sci 103:322–333 Spicer SS, Leppy TJ (1967) Histochemistry of connective tissue mucopolysaccharides in: “The Connective Tissue”. International Academy of Pathology Monograph N7, The Williams and Wilkins Company, Baltimore 1967

Chapter 4

Mast Cell Heterogeneity

4.1 Background Mast cells are strategically located at host/environment interfaces like skin, airways, and gastro-intestinal and uro-genital tracts. Mast cells also populate connective tissues in association with blood and lymphatic vessels and nerves. Mast cells are absent in avascular tissues, such as mineralized bone, cartilage, and cornea. A distinction established in the mouse is that connective tissue mast cells (CTMCs) are constitutive and T independent, while mucosal mast cells (MMCs) are induced and T cell dependent as defined in the intestine and mouse lung (Table 4.1). CTMCs are predominantly found in the skin and in peritoneal cavity, and their granules contain heparin and large amounts of histamine and carboxypeptidase A. In contrast, MMCs are localized mainly in the mucosal layer of the gut and lung and their granules contain chondroitin, and relatively less amount of histamine and carboxypeptidase. In the mouse intestine, mast cells exist in anatomical distributions that are T-cell independent in the submucosa and T-cell dependent in the epithelium (in athymic nude mice intraepithelial mast cells are absent). Human MCsT, containing tryptase alone, correspond to the rodent MMCs while human MCsTC, containing both tryptase and chymase along with other proteases (carboxypeptidase A and cathepsin G), correspond to the rodent CTMCs. MCsT are prevalent in the alveolar septa of the lung and in the small intestinal mucosa. In human intestinal mucosa, mast cells consist of approximately 2–3% of the inflammatory cell infiltrate localized in healthy subjects (Bischoff 2009). In the respiratory system, the greatest concentration of mast cells is found in the trachea and large bronchi, just underneath the epithelium, but some mast cells are present also within the bronchial epithelium. MCsTC predominate in the connective tissue areas, such as skin, submucosa of the stomach and intestine, breast parenchyma, myocardium, thymus, lymph nodes, conjunctiva, and synovium (Crivellato et al. 2004; Irani et al. 1986). In the human skin, mast cells are preferentially located in the most superficial layers where up tenfold more mast cells are found as compared with the subcutis © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_4

25

26 Table 4.1 Human mast cell heterogeneity

4 Mast Cell Heterogeneity

Characteristics

MCsT

MCsTC

Protease content

Tryptase

Tryptase, Chymase

Proteoglycan content

Heparin

Heparin

Granule patterning

Scroll

Lattice

Location

Epitheliun

Connective tissue

Primary role

Host defence

Tissue repair

Activated by antigen

Yes

Yes

Activated by substance P

No

Yes

Responds to PAF

Yes

No

Responds to opiates

No

Yes

(Weber et al. 2003). Mast cells are more numerous around hair follicles, sebaceous and sweat glands, and around small vessels. Small mast cells are found in the subepithelial portion, their size and granule content increasing towards the subcutis. The human skin is an extramedullary reservoir of mast cell precursors, which resides in the connective tissue sheath of hair follicles (Ito et al. 2010). T cell-derived growth factors play an important role in the development and maintenance of human MCsT at mucosal site (Irani et al. 1987). The intraepithelial accumulation of mast cells in bronchi of patients with asthma, which occurs in association with subepithelial infiltrations of activated eosinophils and Th2 cells suggests that mast cells respond to T-cell-derived cytokines in vivo (Pesci et al. 1993). Moreover, in humans with T-cell deficiency intestinal intraepithelial mast cells are absent (Irani et al. 1987). Mast cells release in the surrounding microenvironment a broad array of preformed mediators and signaling molecules affecting the functional profile of different resident tissue cells, like fibroblasts, smooth muscle cells, endothelial cells, epithelial cells and nerve fibres (Gruber et al. 1997; Nilsson et al. 1997; Ribatti et al. 2001a, b; Thabrew et al. 1996). In addition, they synthesize and release both serineand metallo-proteases, which cause extracellular matrix degradation and tissue remodeling (Levi-Schaffer and Pe’Er 2001). These functional properties put mast cells in a central, strategic position to maintain tissue homeostasis (Maurer et al. 2003). The presence of mast cells in connective tissues has been linked to the development of fibrosis through the production of histamine, heparin, tryptase, fibroblast growth factor-2 (FGF-2), TNF-α and TGF-ß, which stimulate the proliferation of myofibroblasts and fibrosis.

4.2 Mast Cells in Thymus

27

4.2 Mast Cells in Thymus In thymus, mast cells localize to the connective tissue of the capsule and interlobular septa, and inside the thymic lobules (Bodey et al. 1987; Kendall 1989). Mast cells are either situated in the perivascular spaces (Kendall 1989) or interspersed among lymphoid and stromal cells, particularly close to peptidergic nerves (Lorton et al. 1990; Muller and Weihe 1991; Weihe et al. 1989). Intrathymic mast cells have been linked to neuro(endocrine)-immune circuits involving mast cell-peptidergic nerve contacts (Lorton et al. 1990; Muller and Weihe 1991; Weihe et al. 1989) and changes in the number of mast cells inside the organ have been reported in a series of experimental conditions related to manipulation of the neuroendocrine axis (Abou-Rabia and Kendall 1994; Barbini et al. 1981). Mast cells synthesize and release a large panel of growth factors and cytokine, including IL-1, IL-2, IL-3, IL-4, IL-6, TNF-α, granulocyte macrophage colony stimulating factor (GM-CSF), and NGF, which stimulate thymocyte and thymic epithelial cell functions (Durkin and Waksman 2001; Soumelis and Liu 2004; Stampachiacchiere et al. 2004). In human and chick thymus, mast cells were restricted to the medulla and to connective tissue septa and their number increased in adult thymus when compared with foetal thymus (Fig. 4.1) (Crivellato et al. 2005; Raica et al. 2010). In the thymoma specimens, mast cells were closer to each other and to the vessels than in normal thymus. The mean distance from vessels and the mean distance from the nearest cell profile were significantly lower than in normal thymus specimens (Raica et al. 2010).

4.3 Mast Cells in Duodenum A significant association has been recognized between villous architecture and the number of mast cells in the small bowel mucosa. Indeed, high values of total and tryptase-reactive mast cells in the lamina propria of human duodenum were associated with normal villous profile while low values were associated with defective or atrophic villi, suggesting participation of mast cells in the network of cellular and molecular signals regulating villous structure and affecting mucosal morphology (Crivellato et al. 2003a, b). Mast cells might affect villous architecture by secreting cytokines, including PDGF, TGF-β, and GM-CSF, which drive intestinal epithelial cell growth and differentiation (Brittan and Wright 2002; Karlsson et al. 2000; Sennikov et al. 2002); by releasing tryptase and chymase affecting stromal and epithelial cell functions, pericryptal extracellular matrix remodeling, and angiogenesis (Blair et al. 1997; Gruber et al. 1989) by releasing angiogenic factors, including as VEGF, FGF-2, histamine, heparin, TNF-α, and IL-8 (Bischoff et al. 1999a, b; Grutzkau et al. 1998; Qu et al. 1998), affecting repair processes and prevent epithelial cell damage (Paris et al. 2001).

28

4 Mast Cell Heterogeneity

Fig. 4.1 Ultrastructural features of two mast cells (mc) lie in the medullary parenchyma of chick embryo thymus, close to a thymic epithelial cell (asterisk). One mast cell shows a prominent Golgi apparatus (curved arrow). Granules present either an irregularly scroll-like pattern (single arrowheads) or a punctate texture (double arrowheads) (Reproduced form Crivellato et al. 2005)

Mast cells may affect villous architecture by exerting neurotrophic and neurogenic effects via NGF secretion (Tsui-Pierchala et al. 2002). Indeed, pericryptal nerves have been implicated in the regulation of crypt epithelial cell migration and differentiation (Bjerknes and Cheng 1999). As myofibroblasts arise in a wide variety of settings concurrently with a local increase in the number of tissue mast cells, Crivellato et al. (2006) calculated the density of both pericryptal fibroblasts and pericryptal mast cells in the mucosa of human duodenum showing normal, defective, or atrophic villous profiles. Results showed that villous architecture was significantly associated with the number of pericryptal fibroblasts and tryptase-, chymase-, c-kit-positive mast cells in the lamina propria. High density of both pericryptal fibroblasts and mast cells was found in intestinal samples with normal villous morphology while lower densities were associated with defective or atrophic villous profiles (Fig. 4.2). In addition, a significant correlation was found between pericryptal fibroblasts density and the density of pericryptal mast cellls, providing morphological support for a cooperation between pericryptal fibroblasts and mast cells in maintaining normal villous architecture (Crivellato et al. 2005; 2006).

4.4 Mast Cells in Mammary Gland

29

Fig. 4.2 Histochemical pictures of alpha-smooth muscle actin-reactive pericryptal fibroblasts (a–c) and tryptase-positive mast cells (d–f) in the crypt lamina propria of duodenal samples with normal (a and d), defective (b and e), and atrophic villi (c and f). In a, pericryptal fibroblasts present a regular location around crypts, which is progressively lost in b and c. Tryptase-reactive mast cells reside in the crypt lamina propria and appear as round to oval cells (Reproduced from Crivellato et al. 2006)

4.4 Mast Cells in Mammary Gland The stroma of mammary gland is especially rich in mast cells particularly around the ducts. Lilla and Werb (2010) demonstrated that mammary glands without or with fewer mast cells had a lower percentage of proliferating cells in both terminal buds (TEBs) and ducts during pubertal development. Mast cells are concentrated around the invading TEBs, and their degranulation and subsequent release of active proteases stimulate epithelial cell proliferation, promoting TEB formation and duct branching, contributing to the complex regulation of cell proliferation in the growing mammary gland. The area surrounding the neck of TEBs consists of a stroma rich

30

4 Mast Cell Heterogeneity

in collagen including other cells, such as fibroblasts, macrophages, an eosinophils, which are also involved in regulation of mammary gland development (Gouon-Evans and Pollard 2002; Gouon-Evans et al. 2000).

4.5 Other Localizations The stroma of salivary glands is especially rich in mast cells (Jaafari-Ashkavandi and Ashraf 2014). In liver, mast cells occur in the capsule, in the connective tissue around the hilum, and in the interlobular spaces (Murata et al. 1973). In heart, mast cells are found underneath pericardium and in connective tissue around the blood vessels (Hellstrom and Holmgren 1950). Mast cells lie between myocytes and in close contact with blood vessels (Patella et al. 1995). Kidney is poor of mast cells, while the capsule and the connective and fat tissue around the pelvis contain many mast cells (Saruta et al. 1977). Numerous mast cells are found in ureter, bladder, and urethra underneath the epithelium but also in the smooth musculature (Cantin and Veilleux 1973). In adrenals, mast cells are present in the capsule and in vicinity of large vessels near the hilum (Majeed 1994). In the hypophysis, mast cells are present in the capsule and within the stroma (Olsson 1968), while in thyroid, parathyroid and pineal gland mast cells are limited to the stroma, in the perivascular areas (Visciano et al. 2015; Jaffray and Anderson 1975; Olsson 1968). In pancreas, mast cells are limited in the stroma in the immediate vicinity of the ducts (Esposito et al. 2001). In ovary, mast cells are scarce within the cortex, but numerous in the medulla, while connective tissue and musculature of oviduct, uterus, and vagina is rich in mast cells (Menzies et al. 2011).

4.6 Mechanistic Insights During normal development, a precise sequence of gene expression events generates signals and outcomes in a controlled manner and at different level, place and time. The interaction between cells and their microenvironment drives differentiating processes. Mast cells express a broad array of cell surface receptors and ligands involved in cell-cell and cell-extracellular matrix adhesion, which mediate the delivery of co-stimulatory signals that interact with different cell types. Once recruited to the tissues, mast cells mature under the influence of cytokines or growth factors released in the local microenvironment (Jamur and Oliver 2011). For example, in the gut epithelium mature mast cells utilize αE integrin, which interacts with E-cadherin at epithelial junctions (Brown et al. 2004), and CXCR2 contributes to recruitment of mast cell progenitors in the lung (Hallgren et al. 2007). Moreover, mast cells are capable of directly influencing T cell migration, differentiation and function through the secretion of TNF-α, chemokines, histamine, and proteases (Galli et al. 2008a, b).

4.6 Mechanistic Insights

31

Many of the physiological functions of mast cells are closely associated with the biological actions of the pre-formed granule compounds (including histamine, setotonin, heparin, tryptase, and chymase), mast cell-derived growth factors, chemokines, cytokines, or lipid-derived mediators, which could contribute to the effects of mast cells in morphogenetic and developmental processes. The localization of mast cells just ahead of around the invading epithelial front during organ development suggest that mast cells may release chemotactic factors which promote epithelial bud outgrowth. Moreover, mast cells play a critical role in tissue remodeling, tissue matrix turnover and renewal. For example, chymases exerts pro-collagenase activity (Saarinen et al. 1994), and are important for processing the pro-enzymes for matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) into active enzymes (Tchougounova et al. 2005; Groschwitz et al. 2013). Mast cells are typically and strategically located nearly external and internal body surfaces such as skin, mucosae, and blood vessels, and it is tempting to speculate that mast cells exert some physiological functions at these sites. Correlated to this vast heterogeneity of cell types, distribution, and anatomical localization, the physiological role of mast cells may be different in different tissues.

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Crivellato E, Nico B, Battistig M et al (2004) The thymus is a site of mast cell development in chicken embryos. Anat Embryol (Berl) 209:243–249 Crivellato E, Finato N, Ribatti D et al (2005) Do mast cells affect villous architecture? facts and conjectures. Histol Histopathol 20:1285–1293 Crivellato E, Finato N, Isola M et al (2006) Number of pericryptal fibroblasts correlates with density of distinct mast cell phenotypes in the crypt lamina propria of human duodenum: implications for the homeostasis of villous architecture. Anat Rec A Discov Mol Cell Evol Biol 288:593–600 Durkin HG, Waksman BH (2001) Thymus and tolerance. is regulation the major function of the thymus? Immunol Rev 182:33–57 Esposito P, Gheorghe D, Kandere K et al (2001) Acute stress increases permeability of the bloodbrain barrier through activation brain mast cells. Brain Res 888:117–127 Galli SJ, Grimbaldeston M, Tsai M (2008a) Immunomodulatory Mast Cells: Negative, as well as Positive, Regulators of Immunity. Nat Rev Immunol 8:478–486 Galli SJ, Tsai M, Piliponski AM (2008b) The development of allergic inflammation. Nature 454:445–454 Gouon-Evans V, Pollard JW (2002) Unexpected deposition of brown fat in mammary gland during postnatal development. Mol Endocrinol 16:2618–2627 Gouon-Evans V, Rothenberg ME, Pollard JW (2000) Postnatal mammary gland development requires macrophages and eosinophils. Development 127:2269–2282 Groschwitz KR, Wu D, Osterfeld H et al (2013) Chymase-mediated intestinal epithelial permeability is regulated by a protese-activating receptor/matrix metalloproteinase-2-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 304:G479–489 Gruber BL, Marchese MJ, Suzuki K et al (1989) Synovial procollagenase activation by human mast cell tryptase dependence upon matrix metalloproteinase 3 activation. J of Clin Invest 84:1657–1662 Gruber BL, Kew RR, Jelaska A et al (1997) Human mast cells activate fibroblasts. J Immunol 158:2310–2317 Grutzkau A, Kruger-Krasagakes S, Baumeister H et al (1998) Synthesis, storage, and release of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by human mast cells: implications for the biological significance of VEGF206. Mol Biol Cell 9:875–884 Hallgern J, Jones TG, Abonia JP et al (2007) Pulmonary CXCR55 regulates VCAM-1 and antigeninduced recruitment of mast cell progenitors. Proc Natl Acad Scie USA 104:20478–20483 Hellstrom B, Holgren H (1950) Numerical distribution of mast cells in the human skin and heart. Acta Anat 10:81–107 Irani AA, Schechter NM, Craig SS et al (1986) Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA 83:4464–4468 Irani AM, Craig SS, DeBlois G et al (1987) Deficiency of the tryptase-positive, chymase-negative mast cell type in gastrointestinal mucosa of patients with defective T lymphocyte function. J Immunol 138:4381–4386 Ito N, Sugawara K, Bodó E et al (2010) Corticotropin-releasing hormone stimulates the in situ generation of mast cells from precursors in the human hair follicle mesenchyme. J Invest Dermatol 130:995–1004 Jaafari-Ashkavandi Z, Ashraf MJ (2014) Increased mast cell counts in benign and malignant salivary gland tumors. J Dent Res Dent Clin Dent Prospects 8:15–20 Jaffray D, Anderson TJ (1975) Mast cells in parathyroid glands. J Clin Pathol 28:765 Jamor MC, Oliver C (2011) Origin, maturation and recruitment of mast cell precursors. Front Biosci 3:1390–1406 Karlsson L, Lindahl P, Heath JK et al (2000) Abnormal gastrointestinal development in PDGFA and PDGFR-(Alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development 127:3457–3466 Kendall MD (1989) The morphology of perivascular spaces in the thymus. Thymus 13:157–164 Levi-Schaffer F, Pe’Er J (2001) Mast cells and angiogenesis. Clin Exp Allergy 31:521–524

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Lilla JN, Werb Z (2010) Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis. Dev Biol 337:124–133 Lorton D, Bellinger DL, Felten SY et al (1990) Substance P innervation of the rat thymus. Peptides 11:1269–1275 Majeed SK (1994) Mast cell distribution in mice. Arzneimittelforschung 44:1170–1173 Maurer M, Theoharides T, Granstein RD et al (2003) What is the physiological function of mast cells? Exp Dermatol 12:886–886 Menzies FM, Shepherd MC, Nibbs RJ et al (2011) The role of mast cells and their mediators in reproduction, pregnancy and labour. Hum Reprod Update 17:383–396 Muller S, Weihe E (1991) Interrelation of peptidergic innervation with mast cells and ED1-positive cells in rat thymus. Brain Behav Immun 5:55–72 Murata K, Okudaira M, Akashio K (1973) Mast cells in human liver tissue. increased mast cell number in relation to the components of connective tissue in the cirrhotic process. Acta Derm Venereol Suppl (Stockh).73:157–165 Nilsson G, Forsberg-Nilsson K, Xiang Z et al (1997) Human mast cells express functional Trka and are a source of nerve growth factor. Eur J Immunol 27:2295–2301 Olsson Y (1968) Mast cells in the nervous system. Int Rev Cytol 24:27–70 Paris F, Fuks Z, Kang A et al (2001) Endothelial Apoptosis as the Primary Lesion Initiating Intestinal Radiation Damage in Mice. Science 293:293–297 Patella VMI, Lamparter B, Genovese A et al (1995) Immunologic and non-immunologic release of histamine and tryptase from human heart mast cells. Inflammat Res 44:22–23 Pesci A, Foresi A, Bertorelli G et al (1993) Histochemical characteristics and degranulation of mast cells in epithelium and lamina propria of bronchial biopsies from asthmatic and normal subjects. Am Rev Respir Dis 147:684–689 Qu Z, Kayton RJ, Ahmadi P et al (1998) Ultrastructural immunolocalization of basic fibroblast growth factor in mast cell secretory granules: morphological evidence for Bfgf release through degranulation. J Histochem Cytochem 46:1119–1128 Raica M, Cimpean AM, Nico B et al (2010) A Comparative study of the spatial distribution of mast cells and microvessels in the foetal, adult human thymus and thymoma. Int J Exp Pathol 91:17–23 Ribatti D, Crivellato E, Candussio L et al (2001a) Mast cells and their secretory granules are angiogenic in the chick embryo chorioallantoic membrane. Clin Exp Allergy 31:602–608 Ribatti D, Vacca A, Nico B et al (2001b) The role of mast cells in tumour angiogenesis. Brit J Haematol 115:514–521 Saarinen J, Kalkkinen N, Welgus HG et al (1994) Activation of human interstitial procollagenase through direct cleavage of the Leu3-Thr4 bond by mast cell chymase. J Biol Chem 269:18134–18140 Saruta T, Kondo K, Ohguro T et al (1977) Mast cells in human kidney cortex. Keio J Med 26:163–169 Sennikov SV, Temchura VV, Kozlov VA et al (2002) The influence of conditioned medium from mouse intestinal epithelial cells on the proliferative activity of crypt cells: role of granulocytemacrophage colony-stimulating factor. J Gastroenterol 37:1048–1051 Soumelis V, Liu Y-J (2004) Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation. Springer Semin Immunopathol 25:325–333 Stampachiacchiere B, Marinova T, Velikova K et al (2004) Altered levels of nerve growth factor in the thymus of subjects with myasthenia gravis. J Neuroimmunol 146:199–202 Tchougounova E, Lundequist A, Fajardo I et al (2005) A key role for mast cell chymase in the activation for pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem 280:9291–9296 Thabrew H, Cairns JA, Walls AF (1996) Mast cell tryptase is a growth factor for human airway smooth muscle. J Allergy Clin Immunol 97:969

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Tsui-Pierchala BA, Milbrandt J, Johnson EM (2002) NGF utilizes c-ret via a novel GFLindependent, inter-RTK signaling mechanism to maintain the trophic status of mature sympathetic neurons. Neuron 33:261–273 Visciano C, Prevete N, Liotti F et al (2015) Tumor-associated mast cells in thyroid cancer. Int J Endocrinol 2015:705169 Weber A, Knop J, Maurer M (2003) Pattern analysis of human cutaneous mast cell populations by total body surface mapping. Br J Dermatol 148:224–228 Weihe E, Müller S, Fink T et al (1989) Tachykinins, calcitonin gene-related peptide and neuropeptide Y in nerves of the mammalian thymus: interactions with mast cells in autonomic and sensory neuroimmunomodulation? Neurosci Lett 100:77–82

Chapter 5

Mast Cell Biology and Functions

5.1 Background In histological preparations, mast cells usually appear as round or elongated cells with a diameter ranging between 8 and 20 μm, depending on the organ examined. Their single nucleus shows round or oval shape and the cytoplasm contains numerous secretory granules that stain metachromatically with thiazine dyes such as toluidine blue. By electron microscopy, mast cells exhibit a non-segmented monolobed nucleus with peripherally condensed chromatin. The cytoplasm contains a few mitochondria, short profiles of the rough endoplasmic reticulum, free ribosomes and numerous membrane-bound, moderately electron-dense secretory granules with an average diameter of 1.5 μm (Dvorak 1991). Secretory granules may present different substructural patterns, such as homogeneous, crystalline, scroll, particle or threadlike or a combination of them. Granule ultrastructure has been partly related to their content of serine proteases. Indeed, granules with the chymase protease preferentially exhibit homogeneous or crystalline substructures whereas granules lacking this protease show mainly a scroll pattern (Schwartz et al. 1987). However, significant granule heterogeneity can be found in any particular tissue and even between granules of a single mast cell. In addition to the typical secretory granules, human and mouse mast cells also contain non-membrane-bound, highly osmiophilic granules, called lipid bodies (Dvorak 1991). They are fewer in number and generally larger than secretory granules, and serve as a significant site for arachidonic acid storage and metabolism. Besides cytoplasmic granules, all mammalian mast cells express common characteristics, including the SCF plasma membrane receptor KIT and the high affinity plasma membrane receptor (FcεRI) binding IgE antibodies. Most of our knowledge on mast cell is derived from mast cell “knock-in” mouse models which have allowed researchers for testing and verifying whether mast cell contribute to specific functions. The Kit-mutant mice, which are deficient in mast cells, has been used in a series of experimental settings (Galli et al. 2005a). The Kit gene encodes for the KIT protein (CD117) or SCF receptor on the surface of mast cells and other cell types, such as germ cells, melanocytes and intestinal Cajal cells © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_5

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(Nocka et al. 1990; Galli et al. 1992; Metcalfe et al. 1997). SCF, or KIT receptor ligand, represents the main survival and developmental factor for mast cells. Lack of expression of a functional KIT receptor due to spontaneous mutation in both copies of Kit, as it occurs in genetically mast cell-deficient WBB6F1-Kit W -Kit W −v mice (W/W v mice), results in a virtual absence of tissue mast cells (Kitamura et al. 1978). Kit W contains a poit mutation that encodes a truncated KIT protein, which lacks the transmembrane domain and is therefore not expressed on the cell surface; Kit W −v encodes a mutation in the KIT tyrosine kinase domain that markedly decreases the kinase activity of the receptor. A Kit-mutant mouse has been characterized more recently, the C57BL/6-Kit W −sh/W −sh mice (Grimbaldeston et al. 2005; Zhou et al. 2007). Kit W −sh contains an inversion mutation of the transcriptional regulatory elements upstream of the Kit transcription start site on mouse chromosome 5 (Galli et al. 2005b). Lack of mast cells in Kit-mutant mice can be selectively repaired by the adoptive transfer of genetically compatible wild-type or mutant mast cells derived from in vitro cultures to create the so called mast cell “knock-in” mice. The cross-linking of IgE with bivalent or multivalent antigen results in the aggregation of FcεRI, which is sufficient for initiating down-stream signal transduction events that activate cell degranulation as well as the de novo synthesis and secretion of lipid mediators and cytokines (Blank and Rivera 2004). Release of preformed and newly formed mast cell products from activated mast cells leads to a series of profound biological effects. For the sake of clearness, the effects of mast cell activation may be conceptualized into two partly overlapping categories, i.e., immunological and non-immunological. Mast cells may also be activated by “alternative”, IgE-independent pathways, such as aggregation of FcγRIII by IgG/antigen complexes, KIT and Toll-like receptor mechanisms, exposure to chemokines, anaphylatoxins C3a and C5a, fragments of fibrinogen and fibronectin (Johnson et al. 1975; Wojtecka-Lukasik and Maslinski 1992; Prodeus et al. 1997; Gommerman et al. 2000; Marshall 2004). When mast cells are activated, they immediately extrude granule-associated substances, such as histamine and proteases. Within minutes, they generate lipid-derived mediators (Brody and Metcalfe 1998). Then, mast cell activation is followed also within ours, by the de novo synthesis of numerous cytokines and chemokines (Galli et al. 2005a). Mast cells have long been regarded as key effector cells in IgEassociated immune responses, including allergic disorders and certain protective immune responses to parasites (Gurish and Austen 2001; Galli et al. 2008a). Consequently, mast cells have mainly been considered in the past for their detrimental role in type I allergic reactions, such as anaphylaxis, hay fever, eczema or asthma. Several lines of evidence, however, indicate that mast cells exert key immunological functions and are critical protagonists in host defence in the context of both innate and adaptive immune responses. In addition, there is growing evidence that mast cells exert distinct non-immunological activities, playing a relevant role in processes like wound healing after injury, tissue homeostasis and remodeling, fibrosis as well as tissue angiogenesis.

5.2 Mast Cell-Derived Secretory Products

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5.2 Mast Cell-Derived Secretory Products Mast cell granules are enveloped by a membrane and are organized around a highly sulphated glycosaminoglycan such as heparin or chondroitin sulphate. When mast cells are activated, they extrude granule-associated substances, such as histamine, immediately and within minutes, generate lipid-derived mediators (Table 5.1) (Galli et al. 2005a). Mast cell activation is followed also, within hours, by the de novo synthesis of numerous cytokines and chemokines (Table 5.1). Secretory granules of mast cells contain crystalline complexes of preformed mediators ionically bound to a matrix of proteoglycans. In the mouse, the proteoglycan content of mast cell granules varies in the different mast cell subtypes. CTMC contain heparin that lacks in MMC. Conversely, MMC express chondroitin sulphates A and B, which are not found in CTMC, whereas both mast cell subtypes store chondroitin sulphate E in their granules (Féger et al. 2002). The dominant proteoglycan in human mast cells is heparin, which constitutes some 75% of the total, with a mixture of chondroitin sulfates making up the remainder (Church and Levi-Schaffer 1997). In humans, the heparin content in MCT and MCTC is roughly the same. Chondroitin sulphate and heparin proteoglycans are thought to bind histamine, neutral proteases, and carboxypeptidases primarily by ionic interactions and, therefore, contribute to

Table 5.1 Mast cell mediators Preformed

• Biogenic amines (histamine, serotonin, dopamine, polyamines) • Proteoglycans (heparin, chondroitin sulphate) • Proteases (tryptase, chymase, matrix metalloproteinases, cathepsin G, carboxypeptidase A3, granzyme B) • Lysosomal enzymes (β-hexosaminidase, β-glucoronidase, β-d-galactosidase, arylsulphatase A, cathepsin B, C, D, E, L) • Renin

De novo synthesized

• Lipid mediators [prostaglandin E2, D2 (PGE2, PGD2), platelet activating factor (PAF), leukotrienes B4, C4 (LTB4, LTC4)] • Cytokines and chemokines • Interleukins (IL1-β, IL2, IL3, IL4, IL5, IL6, IL9, IL11, IL12, IL13, IL16, IL17A, Il18, IL22, IL25, IL33) • Chemokines (CCL-1/I-309; CCL-2/MCP-1; CCL-3/MIP-1α; CCL-4; CCL-5; CCL-7; CCL-8; CCL-9; CCL-11; CCL-17; CCL-20; CCL-22; CXCL-1/GRO-α; CXCL-2; CXCL-8/IL-8; CXCL-10/IP-10) • Angiogenic factors (FGF-2, VEGF-A, PDGF) • Lymphangiogenic factors (VEGF-C, VEGF-D) • Growth factors (NGF, GM-CSF) • Inflammatory cytokines (TNF-α, IFN-γ) • Regulatory cytokine (TGF-β)

Legend PG (Prostaglandin), IL (Interleukin), CCL (Chemokine C–C motif Ligand), CXCL (Chemokine C–X–C motif Ligand), FGF (Fibroblast Growth Factor), VEGF (Vascular Endothelial Growth Factor), PDGF (Platelet Derived Growth Factor), NGF (Nerve Growth Factor), GM-CSF (Granulocyte Macrophage Colony Stimulating Factor), TNF (Tumor Necrosis Factor), IFN (Interferon), TGF (Transforming Growth Factor)

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the packaging and storage of these molecules in the granules. Mice that lack the enzyme N-deacetylase/N-sulphotransferase-2 (NDST-2), which are unable to product fully sulphated heparin, exhibit severe defects in the granule structure of mast cells, with impaired storage of certain proteases and reduced content of histamine (Humphries et al. 1999; Forsberg et al. 1999). During degranulation, the various mediators packaged with proteoglycans dissociate at different rates, histamine very rapidly but tryptase and chymase much more slowly. Histamine, the first discovered mediator in mast cells, is present at a concentration of 1–4 pg/cell in human mast cells. Histamine exerts many effects pertinent to the immediate phase of allergic response, including vasodilation, increased vasopermeability, contraction of bronchial and intestinal smooth muscle cells, and increased mucous production. Histamine mediates its action via the histamine receptors 1–3, which can transduce signals leading to the variety of symptoms associated with acute allergic reactions (Galli et al. 2008a). Mast cells are a rich reservoir of neutral proteases. The major mast cell protease is tryptase, a 130 kD serine protease, which is stored in a fully active form in the granule. It represents the most abundant constituent of human mast cells. Some 10 pg/cell has been detected in mast cells in the lung and up to 35 pg/cell in skin mast cells (Schwartz et al. 1987). Tryptase cleaves various bronchial and intestinal neuropeptides, matrix components as well as IgE molecules, thus possibly down regulating the allergic response (Rauter et al. 2008). In addition, it is emerging as a potent growth factor for fibroblasts, endothelial cells and muscle cells (Blair et al. 1997; Gruber et al. 1997). Chymase, a 30 kD protease, is present within the granules of the MCTC subset of mast cells, in an estimated concentration of 4.5 pg/cell (Schwartz et al. 1987; Metcalfe et al. 1997). Like tryptase, it degrades some neuropeptides and interleukins, and cleaves collagen and other extracellular matrix (ECM) components (Huang et al. 1998). In the mouse, at least five different granule-associated chymases (mMCP-1, mMCP-2, MMCP-3, MMCP-4, MMCP-5) and three different granule-associated tryptases (mMCP-6, mMCP-7, mMMP11/transmembrane tryptase [mTMT]) have been described at the protein level (Huang et al. 1998). There appear to be multiple forms of human tryptases as well (tryptases α, I, II/β, III) (Vanderslice et al. 1990; Miller et al. 1989, 1990). Two other proteases, carboxypeptidase and cathepsin G, have been associated with the MCTC subset. The specific protese content of individual mast cell can vary depending on the mast cell microenvironment. For example, MMC in mice express mMCP-1 and mMCP-2, whereas CTMC express a different pattern of proteases, namely mMCP-3, mMCP-4, mMCP-5, mMCP-6, mMCP-7 and carboxypeptidase (Stevens et al. 1993; Miller and Pemberton 2002). Mast cell proteases play an important role in innate host defence. Tryptase mMCP-6, for instance, has a critical protective function in bacterial and parasite infection. mMCP-6-deficient mice are less able to clear Klebsiella pneumoniae injected into their peritoneal cavities, probably because of less recruitment of neutrophils (Thakurdas et al. 2007). Delayed expulsion of the adult helminth and increased deposition of larvae in muscles occur in mMCP-1-deficient mice infected with Trichinella spiralis (Knight et al. 2000). mMCP-6 as well is important for the clearance of the chronic Trichinella spiralis infection (Shin et al. 2008).

5.2 Mast Cell-Derived Secretory Products

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Preformed substances stored in the secretory granules can be released by two morphologically distinct secretory pathways, referred to as exocytosis (also called “anaphylactic degranulation”) and piecemeal degranulation (or intragranular activation) (Dvorak 2005). Exocytosis consists of a rapid and massive secretory process, which characteristically occurs during IgE-dependent hypersensitivity reactions. In exocytosis, cytoplasmic granule membranes fuse with each other and with the plasma membrane, giving rise to open secretory channels which allow the release of granule contents into the local extracellular environment. Piecemeal degranulation, conversely, represents a particulate mode of mast cell secretion, characterized by a slow discharge of granule contents in a “piecemeal” fashion, without membrane fusion events and granule opening to the cell exterior. This degranulation pattern has frequently been observed in mast cells infiltrating areas of chronic inflammation or tumors (Dvorak 1991). The most important mast cell-derived lipid mediators are cyclooxygenase and lipoxygenase metabolites of arachidonic acid (Galli et al. 2005a). All these products have potent inflammatory activity and can also modulate the release process. The major cyclooxygenase product of mast cells is prostanglandin D2 (PGD2 ), and the major lipooxygenase products derived from mast cells are the sulphiodopeptide leukotrienes (LT): LTC4 and its peptidolytic derivates LTD4 and LTE3 . Human mast cells can also product LTB4 , although in much smaller quantities than PGD2 or LCT4 , and some mast cell populations represent a source of platelet activating factor (PAF). More than thirty different cytokines and chemokines have been shown to be produced by human and mouse mast cells. Mast cell secretory granules contain pools of stored TNF-α which has pleiotropic pro-inflammatory effects (Gordon and Galli 1990, 1991). TNF-α has been implicated in neutrophil recruitment, inducing upregulation of the endothelial-leukocyte adhesion molecule (ELAM-1) (Walsh et al. 1991). TNF-α has also been known to enhance the bactericidal activities of neutrophils (Kenny et al. 1993). Certain mast cell populations may also have preformed stores of VEGF (Boesiger et al. 1998). In addition, human mast cells have the capacity to generate IL-8, thus contributing to neutrophil recruitment (Moller et al. 1993). Under allergic conditions mast cells produce significant amounts of IL-1 that may contribute to lymphatic infiltration (Bochner et al. 1990) and IL-4, essential for the triggering of Th2 lymphocytes that themselves produce IL-4 to initiate inflammatory cell accumulation and B lymphocyte immunoglobulin class switching to IgE (Bradding et al. 1993). Other cytokines involved in mast cells found in normal and in asthmatic airways are IL-5 and IL-6 which, together with IL-4 and IL-13, would enhance Th2-type immune response and eosinophil chemotaxis, thus indicating that mast cells may play an important role in initiating and maintaining the inflammatory response in asthma (Bradding et al. 1995). Interestingly, a unique profile of cytokines is induced depending upon the nature of the stimulus or type of infection. Human intestinal mast cells spontaneously produce pro-inflammatory cytokines such as TNF-α, IL-6 and IL-8 at low levels without stimulation of the cell (Lorentz and Bischoff 2001). Stimulation by IgE receptor cross-linking leads to an enhanced production of pro-inflammatory cytokines and de novo production of Th2 cytokines such as IL-3, IL-5, IL-10 and IL-13. Gram-negative bacteria, in contrast to IgE receptor

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cross-linking, do not induce the release of Th2 cytokines but enhance that of proinflammatory cytokines. Interestingly, mast cells from different anatomical sites are able to generate distinct profiles of cytokine expression. In the tissues of bronchial and nasal mucosae from normal, asthmatic and allergic rhinitis patients, MCT release IL-5, IL-6 and some IL-4, whereas MCTC preferentially express IL-4 but little IL-5 and IL-6. A similar predominant IL-4 pattern is recognizable in skin mast cells which contain both tryptase and chymase (MCTC ). Such differences in the distribution of cytokine expression between subsets of mast cells suggest a difference in the capacity of mast cell subsets to produce various cytokines and therefore a difference in their specific roles in allergic inflammation. Mast cells express an important set of chemokines, which influence recruitment of dendritic cells, lymphocytes, other inflammatory cells and tissue resident cells at sites of tissue inflammation as well as migration of dendritic cells to lymph nodes. Cross-linking of FcεRI on mast cells induces the release of the CCL1 chemokine, which act to recruit Langerhans-type dendritic cells to sites of atopic skin inflammation (Gombert et al. 2005). Mast cells also express CCL19, the ligand for CCR7, a chemokine receptor required for dendritic cell migration (Humrich et al. 2006). Other products of mast cell activation, including CCL5 (RANTES) and TNF-α, can promote dendritic cells migration (Yamazaki et al. 1998). Mast cells also appear to orchestrate the migration of T cells. Upon activation, mast cells express chemoattractants such as LTB4 , IL-16, XCL1 (also called lymphotactin) CCL3 (also called MIP-1α), CCL2 (mMCP-1), CCL5, CCXCL10, CCL19, and CCL21 (Galli et al. 2005b; Sayed et al. 2008). Mast cell-derived LTB4 is essential for the recruitment of both CD4+ and CD8+ effector cells to sites of inflammation (Ott et al. 2003). CXCL8 (IL-8) is another mast cell-derived chemokine which exerts basic functions on inflammatory cell recruitment and endothelial cell activation.

5.3 Mast Cell Immunological Functions (Table 5.2) Mast cells have been recognized as crucial effectors in both innate and adaptive immune responses. This concept mostly derives from studies using mast cell-deficient mice. In these experimental settings, mast cells have been shown to protect against bacteria, fungi, protozoa and perhaps even viruses through the release of proinflammatory and chemotactic mediators (Féger et al. 2002). Indeed, recent reports in the literature indicate that mast cells can mediate a variety of antimicrobial activities. Mast cells, for instance, are able to recognize and kill opsonised bacteria. Salmonella typhimurium coated with the C3b fragment of complement is recognized through complement receptor 3 (CR3) on the mast cell membrane (Sher et al. 1979). In addition, mast cells express several IgG receptors that are involved in the binding of IgGcoated bacteria to the mast cell membrane (Talkington and Nickell 2001). Following their binding to mast cells, osponized bacteria are phagocytosed. Mast cells are a rich source of early-response cytokines, such as TNF-α and IL-4, that are decisive in initiating the immune and inflammatory responses of the host to the invading pathogens

5.3 Mast Cell Immunological Functions …

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(Galli et al. 2005b). Mast cells release TNF-α stored in secretory granules after incubation with bacteria both in vitro and in vivo (Echternacher et al. 1996; Malaviya et al. 1996). In mutant W/W v mice, the absence of mast cells leads to a defective innate immune response against bacteria. In a model of acute septic peritonitis by cecal ligation and puncture, W/W v mice exhibited a dramatically increased mortality compared with the wild-type mice (Echternacher et al. 1996). Remarkably, the adoptive transfer of mast cells to the peritoneum protected the mast cell-deficient mice from the lethal effects of cecal ligation and puncture. Similarly, mast cell-deficient W/W v mice are less protected against experimentally induced lung enterobacterial infections than mast cell-sufficient or mast cell-reconstructed W/W v mice (Malaviya et al. 1996). The impaired killing of bacteria in mast cell-deficient mice was directly correlated with reduced neutrophil infiltration in lungs, partly as a result of lower levels of the mast cell-derived chemotactic TNF-α in these mice. Indeed, TNF-αdeficient mice have increased mortality in the “cecal ligation and puncture” model compared with wild-type mice (Maurer et al. 1998). Recent evidence indicates that mMCP-2, a mouse mast cell serine protease of the chymase type, can contribute to neutrophil recruitment and host survival during cecal ligation and puncture in mice (Orinska et al. 2007). In a mouse model of sepsis, it has been shown that mast cells may decrease neurotensin-induced hypotension as well as sepsis-repeated mortality by degrading neurotensin through the protease neurolysin (Piliponski et al. 2008). Interestingly, other mast cell-derived products, such as leukotriene B4 (LTB4 ), human tryptase β1, macrophage inflammatory protein (MIP)-1α (CCL3), MIP-1β, MIP-2, monocyte chemoattractant protein-1, RANTES (regulated upon activation, normal T-cell expressed and secreted) (CCL5), and IL-8 (CXCL8) appear also to contribute to the influx of neutrophils induced by activated mast cells (Féger et al. 2002). By contrast, mast cells may have deleterious effects during bacterial infections by excessive or inappropriate release of inflammatory mediators leading to detrimental effects to the host. For instance, there are indications that Shiga toxin produced by Shigella dysenteriae may stimulate intestinal mast cells to release excessive amounts of inflammatory mediators derived from arachidonic acid metabolism, in particular LTC4 , leading to diarrhea and dysentery (Pulimood et al. 1998). Mast cells may also trigger inflammation in Helicobacter pylori infection, as mast cell accumulation in the mucosa of patients with gastritis and mast cell degranulation by H. pylori products have been described (Masini et al. 1994; Plebani et al. 1994; Nakajima et al. 1997). In addition, although mast cells are capable to phagocytose and kill various opsonised bacteria, this capacity may be subverted by microbes endocytosed in nonopsonic conditions (Shin et al. 2000). In these cases, the internalized pathogen is sequestered in a mast cell endosomal compartment that escapes acidification and oxygen radical entry. The net result is that the bacteria are not killed by mast cells but remain in the mast cell cytoplasm as an intracellular reservoir (Féger et al. 2002). Mast cells may also contribute to optimal initiation of acquired immunity by orchestrating migration, maturation and function of dendritic cells and by interacting with T and B cells (Nakae et al. 2005). Mast cells promote dendritic cell migration and lymphocyte recruitment mainly through secretion of factors such as histamine,

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Table 5.2 Immunological and non-immunological functions of mast cells Immunological

• • • • • •

Innate defense Initiation of acquired immune reactions IgE-mediated allergy Immune tolerance Autoimmunity (through IL-1 β, IL-4, TNF-α, and VEGF) B cell proliferation and plasma cell maturation (through IL-6 and CD40L stimulation) • T cell recruitment (through histamine, leukotriene B4, and TNF-α) • T reg induction (through MHC-II and OX40L)

Non-immunological

• • • • • •

Wound healing (through TNF-α, VEGF, FGF-2, and MMPs) Tissue remodeling (through tryptase, chymase, and MMPs) Fibrosis Angiogenesis (through VEGF, FGF-2, Ang-1; IL-8, and PDGF) Organogenesis Adipose tissue metabolism (through IL-6, TNF-α, MMP-9, and MCP-1) • Atherosclerosis • Neuroprotection • Neurogenic inflammation (through histamine, tryptase, and NGF)

Legend IL (Interleukin), FGF (Fibroblast Growth Factor), VEGF (Vascular Endothelial Growth Factor), PDGF (Platelet Derived Growth Factor), (MMPs) Matrix metalloproteinases, NGF (Nerve Growth Factor), TNF (Tumor Necrosis Factor), IFN (Interferon), TGF (Transforming Growth Factor), OX40L (CD252), MHC (Major histocompatibility complex), Ang (Angiopoietin), MCP (Monocyte Chemoattractant Protein)

chemokines, LTB4 and TNF (Demeure et al. 2005; Maurer et al. 2006; Jawdat et al. 2006). Mast cells might contribute also to the processing and presentation of bacterial antigens to immune cells. Indeed, mast cells express MHC class I and II molecules, and can process and present antigens in vitro (Kambayashi et al. 2008). Furthermore, they represent sources of co-stimulatory activity by expressing molecules of the B7 family, members of the TNF and TNF receptor families, CD28 and CD40 ligand (Nakae et al. 2006). In addition, they may modulate the amplitude of the inflammatory response by secreting anti-inflammatory products which promote homeostasis, for instance, by limiting endothelin-1-induced toxicity (Maurer et al. 2004). Mast cells can also limit cutaneous responses to chronic UVB irradiation via IL-10 secretion and enhance resistance to snake or honeybee venoms possibly by protease degradation (Metz et al. 2006; Grimbaldeston et al. 2007). In humans, mast cells have long been recognized as crucial effectors in T helper 2 (Th2)-cell-dependent, IgE-associated allergic disorders, such as urticaria, angioedema, allergic rhinitis, atopic dermatitis, bronchospasm and some food allergies. In this context, activated mast cells release Th2 cytokines, namely IL-4, IL-5, IL-9 and IL-13, that polarize the immune reaction and lead to IgE production by B cells. Mast cells suppress immune responses in murine hepatocarcinoma mode by releasing IL-17 and interacting with regulatory T cells and myeloid-derived suppressor cells (MDSCs) (Yang et al. 2010). Tregs modulate the activity of mast cells through an OX40/OX40L-dependent pattern, which prevents their degranulation and

5.3 Mast Cell Immunological Functions …

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enhances their secretion of IL-6 (Gri et al. 2008; Ganeshan and Bryce 2012). The release of histamine from mast cells can inhibit the repression function of treg by H1 receptor (Noubade et al. 2007). Mast cells may play a role in autoimmunity, affecting disorders like arthritis, multiple sclerosis, bullous pemphigoid and Graves’ ophthalmia. Mast cells help initiate rheumatoid arthritis (Lee et al. 2002. In humans, an increased number of mast cells are found in the synovial tissues and fluids of patients with rheumatoid arthritis and at the site of cartilage erosion, reflecting the presence of mast cell chemotactic or survival factors, such as SCF and TGF-β, in the synovial fluid (Olsson et al. 2001). The invading mast cells show ultrastructural signs of cell degranulation and produce several inflammatory mediators, notably TNF-α, IL-1β and VEGF. TNF-α reportedly plays a pivotal role in the pathogenesis of rheumatoid arthritis, especially in its ability to regulate IL-1β expression, this being important for the induction of prostanoid and matrix MMP production by synovial fibroblasts and chondrocytes. In addition, mast cells promote leakage of fluids into the joints, which in turn allows penetration of selftargeted antibodies that might lead to tissue damage by activating the complement cascade (Nigrovic and Lee 2007). Growing evidence suggests that mast cells play a crucial role in the inflammatory process and subsequent demyelinization observed in patients suffering from multiple sclerosis. Indeed, recent results from animal models with experimental autoimmune encephalomyelitis (EAE) clearly indicate that these cells act at multiple levels to influence both the induction and the severity of the disease, possibly by enhancing Th1 cell response through secretion of IL-4 (Gregory et al. 2006; Christy and Brown 2007). Bullous pemphigoid is another human disease whereby mast cells have been proposed to exert a relevant pathogenic role. This autoimmune skin disease is characterized by subepidermal blisters resulting from auto-antibodies against two hemidesmosomal antigens, BP230 and BP180. Intradermal injection of antibodies against BP180 into neonatal mice causes a blistering disease mimicking bullous pemphigoid. Injection of antibodies against BP180 into mast cell-lacking W/W v mice does not induce bullous pemphigoid, nor does the injection into wild-type mice pre-treated with the mast cell stabilizer cromolyn sodium induce it (Chen et al. 2002). Interstitial cystitis has gained increasing attention for an involvement of mast cells in its pathogenesis. Indeed, the presence of activated mast cells in close proximity to suburothelial nerves is a consistent feature of this yet-to-be-clarified urological pathology (Elbadawi 1997). There are also indications that mast cells may implicated in immunological tolerance. Mast cells indeed serve as enforcers for regulatory T cells, turning down the immune system’s reaction to skin allograft possibly by IL-10 secretion (Lu et al. 2006).

5.4 Mast Cell Non-immunological Functions (Table 5.2) There is emerging evidence that mast cells exert relevant functions in tissue homeostasis, remodeling, repair and fibrosis (Dvorak and Kissel 1991; Gruber et al. 1997; Metcalfe et al. 1997, Artuc et al. 1999, 2002; Weller et al. 2006). These functions

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are accomplished by a direct mast cell stimulation of specific connective tissue cell types, in particular fibroblasts, and by the release or activation of a series of ECMdegrading enzymes. The presence of mast cells in connective tissues has been linked to the development of fibrosis through the production of mediators, cyokines, proteases and growth factors, such as histamine, heparin, tryptase, FGF-2, TNF-α and transforming TGF-β, which stimulate the proliferation of myofibroblasts and fibrosis. TGF-β, exerts a variety of effects on wound repair including the induction and/or facilitation of directed cell migration, angiogenesis and granulation tissue formation. In addition, TGF-β exerts a potent chemotactic effect on mast cells (Gruber et al. 1994). Mast cells are capable of both responding to and producing TGF-β. Moreover, latent TGF-β bound to ECM can be released but not activated by mast cell-derived chymase (Taipale et al. 1995). During the process of wounding, mast cell granules released into the tissue are phagocytozed by fibroblasts and endothelial cells and might thus contribute to persistently increased tissue histamine levels (Seibold et al. 1990). Mast cells release PDGF into wounded tissue and thereby influence the healing process from very early stages onward. Tryptases and FGF-2 are potent activators of fibroblast migration and proliferation (Rouss et al. 1991; Artuc et al. 2002). In an in vivo model of wound healing, an increased number of mast cells positively stained for FGF-2 was detected during the fibroproliferative stage (Liebler et al. 1997). Of particular interest is the observation that tryptases can stimulate the synthesis and release of collagen from fibroblasts in culture, as well as provoking secretion of collagenase (Cairns and Walls 1997). Moreover, tryptases cleave fibronectin and type VI collagen. In addition, this class of molecules has the ability to activate the pre-enzyme forms of some MMP and urinary plasminogen activators (uPA). Indeed, these enzymes have been implied to have a major role in tissue degradation. The ability of tryptases to induce the proliferation of airway smooth muscle cells could be of relevance in conditions such as bronchial asthma, in which smooth-muscle cell hyperplasia is a feature (Thabrew et al. 1996). Tryptases may also have a role in tissue repair processes as a growth factor for epithelial cells. Chymases may contribute to the role of mast cells in tissue remodeling by cleaving type IV collagen and by splitting the dermal-epidermal junction. The production of type VIII collagen by human mast cells in vivo may influence repair processes since this collagen is believed to facilitate the assembly of endothelial cells and tubes and its synthesis precedes that of pro-collagen type I. In addition, mast cells contain NGF which actively stimulate neurogenesis after injury. Indeed, in the rat intestinal mucosa, reconstitution of nerve fibers after experimentally-induced inflammation and nerve fiber degeneration is accompanied by a significant increase in mucosal mast cell density (Stead et al. 1991). In addition, mast cells and mast cell-derived TNF can promote elongation of cutaneous nerves during contact hypersensitivity in mice (Kakurai et al. 2006). Mast cells involvement in the pathogenesis of coronary spasm, cardiomyopathy, atherosclerosis and myocardial ischemia has been suggested. It has been shown that chymase cleaves angiotensin I to angiotensin II more effectively than the angiotensinconverting enzyme (Church and Levi-Schaffer 1997). Studies in the canine model of myocardial ischemia and reperfusion, indicate a role for mast cell mediators in initiating the cytokine cascade which is ultimately responsible for neutrophil accu-

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mulation in the ischemic area. In addition, mast cells have been claimed to play a crucial role for leading to the subsequent fibrotic process (Frangogiannis et al. 1998). By using C57BL/6-Kit W−sh/W−sh mice crossed with atherosclerosis-prone mice deficient in low-density lipoprotein receptor, in vivo evidence has been obtained that mast cells are implicated in the atherogenic process, as mast cell absence causes smaller atherosclerotic lesions with fewer inflammatory cell infiltrates (Sun et al. 2007a). Mast cells may also contribute to the pathogenesis of elastase-induced abdominal aortic aneurysms in mice, as C57BL/6-Kit W−sh/W−sh mice fail to develop such aneurysms (Sun et al. 2007b).

References Artuc M, Hermes B, Steckelings MU et al (1999) Mast cells and their mediators in woundhealing—active participants or innocent bystanders? Exp Dermatol 8:1–16 Artuc M, Steckelings M, Henz BM (2002) Mast cell-fibroblast interactions: human mast cells as source and inducer of fibroblast and epithelial growth factors. J Invest Dermatol 118:391–395 Blair RJ, Meng H, Marchese MJ et al (1997) Tryptase is a novel, potent angiogenic factor. J Clin Invest 99:2691–2700 Blank U, Rivera J (2004) The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol 25:266–273 Bochner BS, Charlesworth EN, Lichtenstein LM et al (1990) Interleukin-1 is released at sites of human cutaneous allergic reactions. J Allergy Clin Immunol 86:830–839 Boesiger J, Tsai M, Maurer M et al (1998) Mast cells can secrete vascular Permeabilità factor/vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of Fcε receptor I expression. J Exp Med 188:1135–1145 Bradding P, Feather IH, Wilson S et al (1993) Immonolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in Human allergic mucosal inflammation. J Immunol 151:3853–3865 Bradding P, Okayama Y, Howzrth PH et al (1995) Heterogeneity of human mast cells based on cytokine content. J Immunol 155:297–307 Brody D, Metcalfe DD (1998) Mast cells: a unique and functional diversity. Clin Exp Allergy 28:1167–1170 Cairns JA, Walls AF (1997) mast cell tryptase stimulate the synthesis of Type I Collagen in human lung fibroblasts. J Clin Invest 99:1313–1321 Chen R, Fairley JA, Zhao ML et al (2002) Macrophages, but not T and B lymphocytes, are critical for subepidermal blister formation in experimental bullous pemphigoid: macrophage-mediated neutrophil infiltration depends on mast cell activation. J Immunol 169:3987–3992 Christy AL, Brown MA (2007) The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J Immunol 179:2673–2679 Church M, Levi-Schaffer F (1997) The human mast cell. J Allergy Clin Immunol 99:155–160 Demeure CE, Brahimi K, Hacini F et al (2005) Anopheles mosquito bites activate cutaneous mast cells leading to a local inflammatory response and lymph node hyperplasia. J Immunol 174:3932–3940 Dvorak AM (1991) Basophil and mast cell degranulation and recovery. In: Harris JR (ed), vol 4. Plenum Press, New York (Blood Cell Biochem) Dvorak AM (2005) ultrastructural studies of human basophils and mast cells. J Histochem Cytochem 53: 1043–1070

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Dvorak AM, Kissell S (1991) Granule changes of human skin mast cells characteristic of piecemeal degranulation and associated with recovery during wound healing in situ. J Leukoc Biol 49:197–210 Echternacher B, Männel DN, Hültner L (1996) Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381:75–77 Elbadawi A (1997) Interstitial cystitis: a critique of current concepts with a new proposal for pathologic diagnosis and pathogenesis. Urology 49:14–40 Féger F, Varadaradjalou S, Gao Z et al (2002) The role of mast cells in host defense and their subversion by bacterial pathogens. Trends Immunol 23:151–158 Forsberg E, Pejler G, Ringvall M et al (1999) Abnormal mast cells in mice deficient in a heparinsynthesizing enzyme. Nature 400:773–776 Frangogiannis NG, Lindsey ML, Michael LH et al (1998) Resident cardiac mast cells degranulate and release preformed TNF-A, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion. Circulation 98:699–710 Galli SJ, Tsai M, Gordon JR et al (1992) Analyzing mast cell development and function using mice carrying mutations at W/C-Kit or Sl/MGF (SCF) Loci. Ann N Y Acad Sci 664:69–88 Galli SJ, Kalesnikoff J, Grimbaldeston MA et al (2005a) Mast cells as “Tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 23:749–786 Galli SJ, Nakae S, Tsai M (2005b) Mast cells in the development of adaptive immune responses. Nat Immunol 6:135–142 Galli SJ, Grimbaldeston M, Tsai M (2008) Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 8:478–486 Ganeshan K, Bryce PJ (2012) Enhance mast cell production of IL-6 via surface-bound TGFβ. J Immunol 188:594–603 Gombert M, Dieu-Nosjean MC, Winterberg F et al (2005) CCL1-CCR44 interactions: an axis mediating the recruitment of T cells and langerhans-type dendritic cells to sites of atopic skin inflammation. J Immunol 174:5082–5091 Gommerman JL, Oh DY, Zhou X et al (2000) A role for CD21/CD35 and CD19 in responses to acute septic peritonitis: a potential mechanism for mast cell activation. J Immunol 165:6915–6921 Gordon JR, Galli SJ (1990) Mast cells as a source of both preformed and immunologically inducible TNF-A/Cachectin. Nature 346:274–276 Gordon JR, Galli SJ (1991) Release of both preformed and newly synthesized Tumor Necrosis Factor Alpha (TNF-A)/Cachectin by mouse mast cells stimulated via the Fcεri. A mechanism for the sustained action of mast cell-derived TNF-A during IgE-dependent biological responses. J Exp Med 174:103–107 Gregory GD, Raju SS, Winandry S et al (2006) Mast Cell IL-4 expression is regulated by Ikaros and influences encephalitogenic TH 1 responses in mice. J Clin Invest 116:1327–1336 Gri G, Piconese S, Frossi B et al (2008) CD4+ CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 29:771–781 Grimbaldenston MA, Nakae S, Kalesnikoff K et al (2007) mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with Ultraviolet B. Nat Immunol 8:1095–1104 Grimbaldeston MA, Chen CC, Piliponski AM et al (2005) Mast cell-deficient W-Sash C-Kit mutant Kitw-Sh/W-Sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167:835–848 Gruber BL, Marchese MJ, Kew RR (1994) Transforming growth factor-β1 mediates mast cell chemotaxis. J Immunol 152:5860–5867 Gruber BL, Kew RR, Jelaska A et al (1997) Human mast cells activate fibroblasts. J Immunol 158:2310–2317 Gurish MF, Austen KF (2001) The diverse role of mast cells. J Exp Med 194:F1–F5 Huang C, Sali A, Stevens RL (1998) Regulation and function of mast cell proteases in inflammation. J Clin Immunol 18:169–183

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Humphries DE, Wong GW, Friend DS et al (1999) Heparin is essential for the storage of specific granule proteases in mast cells. Nature 400:769–772 Humrich JY, Humrich JH, Averbeck M et al (2006) Mature monocyte-derived dendritic cells respond more strongly to CCL19 than to CXCL12: consequences for directional migration. Immunology 117:238–247 Jawdat DM, Rowden G, Marshall JS (2006) Mast cells have a pivotal role in TNF-independent lymph node hypertrophy and the mobilization of langerhans cells in response to bacterial peptidoglycan. J Immunol 177:1755–1762 Johnson AR, Hugli TE, Müller-Eberhard HJ (1975) Release of histamine from rat mast cells by the complement Peptides C3a and C5a. Immunology 28:1067 Kakurai M, Monteforte R, Suto H et al (2006) mast cell-derived tumor necrosis factor can promote nerve fiber elongation in the skin during contact hypersensitivity in mice. Am J Pathol 169:1713–1721 Kambayashi T, Baranski JD, Baker RG et al (2008) Indirect involvement of allergen-captured mast cells in antigen presentation. Blood 111:1489–1496 Kenny PA, Mc Donald PJ, Finlay-Jones JJ (1993) The effect of cytokines on bactericidal activity of murine neutrophils. FEMS Immunol Med Microbiol 7:271–279 Kitamura Y, Go S, Hatanaka K (1978) Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 52:447–452 Knight PA, Wright SH, Lawrence CE et al (2000) Delayed expulsion of the nematode trichinella spiralis in mice lacking the mucosal mast cell-specific granule chymase, mause mast cell Protease1. J Exp Med 192:1849–1856 Lee DM, Friend DS, Gurish MF et al (2002) Mast cells: a cellular link between autoantobodies and inflammatory arthritis. Science 297:1689–1692 Liebler JM, Picou MA, Qu Z et al (1997) Altered immunohistochemical localization of basic fibroblast growth factor after bleomycin-induced lung injury. Growth Factors 14:25–38 Lorentz A, Bischoff SC (2001) Regulation of human intestinal mast cells by stem cell factor and IL-4. Immunol Rev 179:57–60 Lu LF, Lind EF, Gondek DC et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002 Malaviya R, Ikeda T, Ross E et al (1996) Mast cell modulation of neurtophil influx and bacterial clearance at sites of infection through TNF-α. Nature 381:77–80 Marshall JS (2004) Mast-cell responses to pathogens. Nat Rev Immunol 4:787–799 Masini E, Bechi P, Dei R et al (1994) Helicobacter pylori potentiates histamine release from rat serosal mast cells induced by bile acids. Dig Dis Sci 39:1493–1500 Maurer M, Wedemeyer J Metz M et al (2004) Mast cells promote homeostasis by limiting Endothelin-1-Induced toxicity. Nature 432: 512–516 Maurer M, Echternacher B, Hültner L et al (1998) The c-kit ligand, stem-cell factor, can enhance innate immunity through effects on mast cells. J Exp Med 188:2343–2348 Maurer M, Lopez Kostka S, Siebenhaar F et al (2006) Skin mast cells control T cell-dependent host defence in leishmania major infections. FASEB J 20:2460–2467 Metcalfe DD, Baram D, Mekori YA (1997) Mast cells. Physiol Rev 77:1033–1079 Metz M, Piliponsky AM, Chen CC et al (2006) Mast cells can enhance resistance to Snake and Honeybee venoms. Science 313:526–530 Miller HR, Pemberton AD (2002) Tissue-specific expression of mast cell granule serine proteinases and their role in inflammation in the lung and gut. Immunology 105:375–390 Miller JS, Westin EH, Schwartz LB (1989) Cloning and characterization of complementary DNA for Human tryptase. J Clin Invest 84:1188–1195 Miller JS, Moxley G, Schwartz LB (1990) Cloning and characterization of a second complementary DNA for Human tryptase. J Clin Invest 86:864–870 Moller A, Lippert U, Lessmann D et al (1993) Human mast cells produce IL-8. J Immunol 151:3261–3266

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Nakae S, Suto H, Hakurai M et al (2005) Mast cells enhance t cell activation: importance of mast cell-derived TNF. Proc Natl Acad Sci USA 102:6467–6472 Nakae S, Suto H, Iikura M et al (2006) Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 176:2238–2248 Nakajima S, Krishnan B, Ota H et al (1997) Mast-cell involvement in gastritis with or without Helicobacter pylori infection. Gastroenterol 113:746–754 Nigrovic PA, Lee DM (2007) Synovial mast cells: role in acute and chronic arthritis. Immunol Rev 217:19–37 Nocka K, Tan JC, Chiu E et al (1990) Molecular bases of dominant negative and loss of function mutations at the Murine C-Kit/White spotting locus, W37, Wv, W41 and W. EMBO J 9:1805–1813 Noubade R, Milligan G, Zachary JF et al (2007) Histamine receptor H1 is required or TCR-mediated p38 MAPK activation and optimal IFNγ production in mice. J Clin Invest 117:3507–3518 Olsson N, Ulfgren AK, Nilsson G (2001) Demonstration of mast cell chemotactic activity in synovial fluid from rheumatoid patients. Ann Rheum Dis 60:187–193 Orinska Z, Maurer M, Mirghomizadeh F et al (2007) IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. Nat Med 13:927–934 Ott VL, Cambier JC, Kappler J et al (2003) Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4 . Nat Immunol 4:974–981 Piliponsky AM, Chen CC, Nishimura T et al (2008) Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis. Nat Med 14:392–398 Plebani M, Basso D, Vianello F et al (1994) Helicobacter pylori activates gastric mucosal mast cells. Dig Dis Sci 39:1592–1593 Prodeus AP, Zhou X, Maurer M et al (1997) Impaired mast cell-dependent natural immunity in complement C3-deficient mice. Nature 390:172–175 Pulimood AB, Mathan MM, Mathan VI (1998) Quantitative and ultrastructural analysis of rectal mucosal mast cells in acute infectious diarrhea. Dig Dis Sci 43:2111–2116 Rauter I, Krauth MT, Westritschnig K et al (2008) Mast cell-derived proteases control allergic inflammation through cleavage of IgE. J Allergy Clin Immunol 121:197–202 Ruoss SJ, Hartmann T, Caughey GH (1991) Mast cell tryptase is a mitogen for cultured fibroblasts. J Clin Invest 88:493–499 Sayed BA, Christy A, Quirion MR et al (2008) The master switch: the role of mast cells in autoimmunity and tolerance. Annu Rev Immunol 26:705–739 Schwartz LB, Irani AA, Roller K et al (1987) Quantitation of histamine, tryptase and chymase in dispersed Human T and TC mast cells. J Immunol 138:2611–2615 Seibold JR, Giorno RC, Claman HN (1990) Dermal mast cell degranulation in systemic sclerosis. Arthritis Rheum 33:1702–1709 Sher A, Hein A, Moser G et al (1979) Complements receptors promote the phagocytosis of bacteria by rat peritoneal mast cells. Lab Invest 41:490–499 Shin JS, Gao Z, Abraham SN (2000) Involvement of cellular caveolae in bacterial entry into mast cells. Sci 289:785–788 Shin K, Watts GF, Oettgen HC et al (2008) Mouse mast cell tryptase Mmcp-6 is a critical link between adaptive and innate immunity in the chronic phase of trichinella spiralis infection. J Immunol 180:4885–4891 Stead RH, Kosecka-Janiszewska U, Oestreicher AB et al (1991) Remodeling of B-50 (GAP-43)and NSE-immunoreactive mucosal nerves in the intestines of rats infected with nippostrongylis brasiliensis. J Neurosci 11:3809–3821 Stevens RL, Friend DS, McNeil HP et al (1993) Stran-specific and tissue-specific of mouse mast cell secretory granule proteases. Proc Natl Acad Sci USA 91:128–132 Sun J, Sukhova GK, Wolters PJ et al (2007a) Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med 13:719–724 Sun J, Sukhova GK, Yang M et al (2007b) Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J Clin Invest 117:3359–3368

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Taipale J, Lohi J, Saarinen J et al (1995) Human mast cell chymase and leukocyte elastase release latent transforming growth factor Beta-1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem 270:4689–4696 Talkington J, Nickell SP (2001) Role of Fgγ receptors in triggering host-cell activation and cytokine release by borrelia burgdorferi. Infect Immun 69:413–419 Thabrew H, Cairns JA, Walls AF (1996) Mast cell tryptase is a growth factor for human airway smooth muscle. J Allergy Clin Immunol 97:969 Thakurdas SM, Melicoff E, Sansores-Garcia L et al (2007) The mast cell restricted tryptase Mmcp-6 has a critical immunoprotective role in bacterial infection. J Biol Chem 282:20809–20815 Vanderslice P, Ballinger SM, Tam EK et al (1990) Human mast cell tryptase: multiple cdnas and genes reveal a multigene serine protease family. Proc Natl Acad Sci USA 87: 3811–3815 Walsh LJ, Trinchieri G, Waldorf HA et al (1991) Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci USA 88:4220–4224 Weller K, Foitzik K, Paus R et al (2006) Mast cells are required for normal healing of skin wounds in mice. FASEB J 20:2366–2368 Wojtecka-Lukasik E, Maslinski S (1992) Fibronectin and fibrinogen degradation products stimulate PMN-leukocytes and mast-cell degranulation. J Physiol Pharmacol 43:173–181 Yamazaki S, Yokozechi H, Satoh T et al (1998) TNF-Alpha, RANTES, and MCP-1 are major chemoattractants in murine langerhans cells to the regional lymoh nodes. Exp Dermatol 7:35–41 Yang Z, Zhang B, Li D et al (2010) Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS ONE 5:e8922 Zhou JS, Xing W, Friend DS et al (2007) Mast cell deficiency in Kit(W-Sh) mice does not impair antibody-mediated arthritis. J Exp Med 204:2797–2802

Chapter 6

Mast Cells in Arteriogenesis

6.1 Background Arteriogenesis is defined as the growth of functional collateral arteries from preexisting arterio-arteriolar anastomoses. It is induced as a consequence of stenosis or occlusion of a major artery. Arterial occlusions often occur in patients who have one or more cardiovascular risk factors, influencing arteriogenic capacity, together with hypercholesterolemia, hypertension, tobacco use, hyperglycemia, obesity, and advanced age all impair collateral artery development (de Groot et al. 2009). Atherosclerosis leads to progressive narrowing and occlusion of conductance arteries, and arterial occlusion prompts an adaptive response of the organisms to compensate for perfusion deficits. Altered blood flow through collateral anastomoses is the initial trigger. The increase in shear stress promotes vessel enlargement, which is stimulated by activation of nitric oxide (Tronc et al. 1996). Two phases of arteriogenesis are described, the proliferating and remodeling phases. Proliferation of the endothelium is followed by smooth muscle cell proliferation, disruption of the lamina elastica interna, migration of vascular smooth muscle cells to form a new neointima, tissue lysis, and cell death of the perivascular tissue to create the space for the growing and expanding new artery. In postnatal life, arteriogenesis refers to anatomic transformation of preexisting arterioles with increasing lumen area and wall thickness, due to a thick muscular layer and purchasing of visco-elastic and vasomotor capacities (Conway 2001). Arteriogenesis differs from angiogenesis in several aspects, the most important being the dependence of angiogenesis on hypoxia and the dependence of arteriogenesis on inflammation. Arteriogenesis occurs in non-hypoxic tissue. After occlusion of the femoral artery, it is detectable neither an increased expression of hypoxia inducible factor-1 alpha (HIF-1α) RNA nor an up-regulation of the HIF-1 controlled VEGF-gene expression (Deindl et al. 2001). There are almost two different modalities of formation of collateral arteries: (i) artery-to-artery anastomosis bypass the capillary bed to provide blood flow to tissues served by an occluded artery. Numerous connections have been demonstrated © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_6

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between branches of the same and of different coronary arteries in human hearts. (ii) arteriole-to-arteriole anastomosis, interconnecting small portion of arterioles of neighboring arterial trees. In physiological conditions, as a result of chronic exercise or muscle loading, there is an increase in the number and length of distal arterioles, with extension of an arterial tree (Hansen-Smith et al. 2001), while in pathological conditions, arteriogenesis is associated to a degradation of the basement membrane by MMP-2 and MMP-9 (Cai et al. 2000), a modification of smooth muscle cells from a contractile to a proliferative phenotype associated with loss of desmin (Wolf et al. 1998) and an inflammatory reaction around vessels.

6.2 Factors Involved in Angiogenesis and Arteriogenesis VEGF/VEGFR-2 signaling pathway controls endothelial cell function in both angiogenesis and arteriogenesis. Arterial differentiation occurs in angioblasts exposed to higher VEGF concentration, whereas angioblasts less exposed differentiate into venous vessels (Simon and Eichmann 2015). In both developmental and adult arteriogenesis VEGF activation of extracellular signal regulating kinase ½ (ERK ½) induces endothelial cell proliferation, network formation and increased vessel lumen size. The activation of this signaling is modulated by neuropilin-1 (NRP-1) (Lanahan et al. 2013; Ren et al. 2010) while TGFα, VEGF, and FGF-2 stimulate angiogenesis through proliferation of endothelial cells, TGF-β, GM-CSF, monocyte chemoattractant protein-1 (MCP-1) and FGF-2 stimulate arteriogenesis through proliferation of smooth muscle cells (van Royen, 2001). FGF-2 and PDGF stimulate both angiogenesis and arteriogenesis. Kastrup (2001) demonstrated elevated levels of circulating angiogenic factors in ischemic injury (ischemic heart disease, stroke, or limb ischemia). Fluid shear stress stimulates arteriogenesis; biomechanical forces exerted by blood flow on the endothelium are involved in modulation of endothelial cell phenotype and blood vessel remodeling (Topper and Gimbrone 1999). Pulsatile shear stress (Buschmann et al. 2010) and circumferential stress (Zheng et al. 2008) activates the cascade of events that leads to development of a collateral circulation (Scholz et al. 2002). Laminar shear stress has been shown to induce a variety of endothelial activation genes, which leads to a general predisposition to arteriogenesis while distributed shear stress tends to suppress endothelial activation genes, which results in quiescence combined with a general anti-apoptotic and anti-inflammatory state. In vivo studies suggest that arteriogenesis can occur when the mechanical environment both inside and outside the cell is changing (Egginton et al. 2001), while other studies have supported this model by suggesting that increases in shear rate function as the primary signal for arteriogenesis (Resnick et al. 2003). The increased flow causes endothelial cell proliferation, with luminar expansion and release of platelet endothelial cell adhesion molecule (PECAM)-1 (Chen et al. 2010), MCP-1, -intracellular adhesion molecule-1 (ICAM-1) and vascular

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cell adhesion molecule-1 (VCAM-1). The up-regulation of adhesion molecules is critical in induction of collateral growth through the recruitment of leukocytes, including monocytes, as well as resident macrophages (Takeda et al. 2011), which, in turn, promote arteriogenesis secreting MMPs, chemokines and growth factors (Ribatti et al. 2007a, b).

6.3 Inflammatory Cells in Arteriogenesis Monocytes are recruited by MCP-1and by the major MCP-1 receptor, the CCchemokine receptor-2 (CCR-2) (Heil 2004). Their binding to the collateral surface is mediated by integrin receptors including macrophage-1 Ag (Mac-1) and lymphocyte function-associated Ag-1 (LFA-1). After adhesion, they migrate in the deeper parts of the collateral wall. Monocytes-macrophages are involved in the proliferation of the vascular wall and in the vascular wall remodeling by releasing growth factors, proteases, and chemokines (Kusch et al. 2002). Macrophages accumulate along collateral artery within 12 h after ligation and disappear over time (Scholz et al. 2000). CCR-2 is expressed also on activated T-cells and lymphocytes appear in proximity to growing collaterals (Stabile 2003). CD4-positive cells deletion resulted in impaired revascularization after hind limb legation (Stabile 2003). CD8-positive cells are first recruited to the collateral vessel and then influence CD4-positive cells and monocytes recruitment through the release of interleukin-16 (IL-16) (Stabile 2005). Also natural killer (NK) cells are involved in the development of collateral artery (van Weel et al. 2007). Controversial is the role of the bone marrow-derived progenitors recruited to growing vessels in arteriogenesis (Kinnaird 2004; Ziegelhoeffer 2004), while endothelial precursor cells are incorporated into activated endothelium; in fact, they possess the ability to migrate, colonize, proliferate, and, ultimately, differentiate into endothelial lineage cells acquiring acquire mature endothelial cell characteristics (Hur et al. 2003).

6.4 Mast Cells in Arteriogenesis Mast cells are localized in the perivascular spaces of arteries, where they synthesize vasoactive substances and growth factors, involved in arterial remodeling (Cao et al. 2003). Wolf et al. (1998) suggested a larger presence of mast cells during the initiation and growth phases, when these cells are able to release a large amount of proteolytic enzymes, cytokines and growth factor able to stimulate endothelial cell migration and proliferation, with a disappearance as the collateral vessels mature. Heissig et al. (2005) demonstrated in mast cell deficient mice that these cells play a significant role in neovascularization after hindlimb ischemia through secretion of

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VEGF and MMP-9. They proposed a mast cell-mediated mobilization of progenitor cells from bone marrow during ischemia that could be enhanced by low-dose radiation. In fact, mast cells express the SDF-1α receptor CXCR-4 as well as the SCF receptor c-kit and both ligands are able to recruit stem cells promoting neovascularization. SCF is required for the differentiation and maturation of mast cells; in fact, in mice carrying a mutation in their c-kit gene, which results in complete mast cell deficiency (Kitamura et al. 1978). Moreover, mast cells stimulate arteriogenesis recruiting neutrophils as well as monocytes and T cells. Chillo et al. (2016) used an experimental murine hindlimb model in which femoral artery ligation resulted in collateral artery growth in the upper limb (Limbourg et al. 2009). They demonstrated that mast cells degranulate around growing collateral arteries. Moreover, pharmacological activation of mast cells with compound 48/80 (c48/80) and the c-kit ligand SCF, which triggers mast cell maturation and recruitment, enhanced perfusion recovery and arteriogenesis (Chillo et al. 2016). C48/80 treatment enhanced mast cell degranulation and reduction of the number of detectable mast cells around the collateral arteries. Combined administration of c48/80 and diprotin A (dip A, a protease inhibitor acting as an inhibitor of dipeptidyl aminopeptidase IV) further increased perfusion recovery, whereas combined treatment with c48/80, dipA, and SCF showed no further additive effect (Chillo et al. 2016). Finally, Cromolyn (an inhibitor of the release of mediators of inflammation induced by specific antigens as well as not specific mechanisms from mast cells) treatment abolished the stimulating effect of dip A and c48/80, indicating that the majority of recruited cells were mast cells that promoted arteriogenesis by their degranulation products (Chillo et al. 2016). Mast cells play a crucial role also in the development of atherosclerotic plaque through the release of a large amount of inflammatory mediators, including histamine, heparin, proteases, and cytokines, contributing to the initiation and progression of atherosclerosis and ultimately, leading to the destabilization and rupture of advanced atherosclerotic plaque (Ribatti et al. 2008).

6.5 Perspectives The role of mast cells in arteriogenesis is largely unexplored. Mast cells together with other inflammatory cells, including monocytes-macrophages, lymphocytes, and NK cells may be involved in this process. Mast cells are localized in the close vicinity of the vascular wall. This location of mast cells in the perivascular space is promoted by the endothelial cell release of SCF (Mierke et al. 2000). Moreover, mast cells accumulate in the adventitia of growing collaterals (Schaper and Scholz 2003). The occurrence of mast cells at the vascular wall, particularly their location at branch points might be explained by the fact that mast cells can be recruited by angiogenic factors (Heissig et al. 2005). In these anatomical sites, mast cells synthesize and release a number of factors which exert either stimulatory or inhibitory effect on blood vessel formation. The list

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of pro-angiogenic factors exceeds the record on anti-angiogenic mediators and mast cells are regarded as tissue-homing inflammatory cells playing a crucial role in the amplification of the angiogenic response. Furthermore, degranulation of mast cells and their release of growth factors and chemokines/cytokines provides a necessary environment for the recruitment of leukocytes. When mast cell granules were cultured with endothelial cells, significant levels of MCP-1 were released and gene expression of MCP-1 mRNA levels were also increased in comparison to control values (Kinoshita 2005). As a consequence, MCP-1 recruit monocytes which leave the vessel, become macrophages with growth factors. Also TNF-α released by mast cells promotes leukocyte recruitment and is an important mediator of inflammation (Bradley 2008) and during arteriogenesis, TNFα modulates collateral artery growth by activating the p55 receptor of endothelial cells (Hoefer 2002). The role of MMPs in angiogenesis is related to the degradation of the vascular basement membrane and in the remodeling of the extracellular matrix which allows leukocytes to migrate and to invade the surrounding tissue, and the importance of MMP-2 and 9 has been described in arteriogenesis (Wolf et al. 1998). Chillo et al. (2016) have demonstrated that the pharmacological treatment of mice with dip A and with the compound 48/80 encouraged the enlargement of collateral arteries, improved the blood supply of distal muscles and reduced the ischemia related damage of distal muscle tissue after the occlusion of a major artery. In this context, the beneficial consequences of mast cell recruitment and degranulation could also be exploited clinically by an application of dip A and compound 48/80 in patients with vascular occlusive diseases.

References Bradley JR (2008) TNF-mediated inflammatory disease. J Pathol 214:149–160 Buschmann I, Pries A, Styp-Rekowska B et al (2010) Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis. Development 137:2187–2196 Cai W-J, Vosschulte R, Afsah-Hedjri A et al (2000) Altered balance between extracellular proteolysis and antiproteolysis is associated with adaptive coronary arteriogenesis. J Mol Cell Cardiol 32:997–1011 Cao R, Bråkenhielm E, Pawliuk R et al (2003) Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med 9:604–613 Chen Z, Rubin J, Tzima E (2010) Role of PECAM-1 in arteriogenesis and specification of preexisting collaterals. Circ Res 107:1355–1363 Chillo O, Kleinert Eike C, Lautz T et al (2016) Perivascular mast cells govern shear stress-induced arteriogenesis by orchestrating leukocyte function. Cell Rep 16:2197–2207 Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507–521 de Groot D, Pasterkamp G, Hoefer IE (2009) Cardiovascular risk factors and collateral artery formation. Eur J Clin Invest 39:1036–1047 Deindl E, Buschmann I, Hoefer IE et al (2001) Role of Ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit. Circ Res 89:779–786 Egginton S, Zhou AL, Brown MD et al (2001) Unorthodox angiogenesis in skeletal muscle. Cardiovasc Res 49:634–646

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Hansen-Smith F, Egginton S, Zhou AL et al (2001) Growth of arterioles precedes that of capillaries in stretch-induced angiogenesis in skeletal muscle. Microvasc Res 62:1–14 Heil M, Ziegelhoeffer T, Wagner S et al (2004) Collateral artery growth (Arteriogenesis) after experimental arterial occlusion is impaired in mice lacking CC-Chemokine Receptor-2. Circ Res 94:671–677 Heissig B, Rafii S, Akiyama H et al (2005) Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9–mediated progenitor cell mobilization. J Exp Med 202:739–750 Hoefer IE (2002) Direct evidence for tumor necrosis factor-alpha signaling in arteriogenesis. Circulation 105:1639–1641 Hur J, Yoon CH, Kim HS et al (2003) Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscl Thromb Vasc Biol 24:288–293 Kastrup J, Jørgensen E, Drvota V (2001) Vascular growth factor and gene therapy to induce new vessels in the ischemic myocardium. Therapeutic angiogenesis. Scan Cardiovasc J 35:291–296 Kinnaird T (2004) Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 94:678–685 Kinoshita M (2005) Mast cell tryptase in mast cell granules enhances MCP-1 and Interleukin-8 production in human endothelial cells. Arterioscl Thromb Vasc Biol 25:1858–1863 Kitamura Y, Go S, Hatanaka K (1978) Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 52:447–452 Kusch A, Tkachuk S, Lutter S et al (2002) Monocyte-expressed urokinase regulates human vascular smooth muscle cell migration in a coculture model. Biol Chem 383:217–221 Lanahan A, Zhang X, Fantin A et al (2013) The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev Cell 25:156–168 Limbourg A, Korff T, Napp LC et al (2009) Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia. Nat Prot 4:1737–1748 Mierke CT, Ballmaier M, Werner U et al (2000) Human endothelial cells regulate survival and proliferation of human mast cells. J Exp Med 192:801–812 Ren B, Deng Y, Mukhopadhyay A et al (2010) ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish. J Clin Invest 120:1217–1228 Resnick N, Yahav H, Shay-Salit A et al (2003) Fluid shear stress and the vascular endothelium: for better and for worse. Prog Biophys Mol Biol 81:177–199 Ribatti D, Nico B, Crivellato E et al (2007a) Macrophages and tumor angiogenesis. Leukemia 21:2085–2089 Ribatti D, Finato N, Crivellato E et al (2007b) Angiogenesis and mast cells in human breast cancer sentinel lymph nodee with and without micrometastasis. Histopathology 51:837–842 Ribatti D, Levi-Schaffer F, Kovanen PT (2008) Inflammatory angiogenesis in atherogenesis—a double-edged sword. Ann Med 40:606–621 Schaper W, Scholz D (2003) Factors regulating arteriogenesis. Arterioscler Thromb Vasc Biol 23:1143–1151 Scholz D, Ito W, Fleming I et al (2000) Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (Arteriogenesis). Virchows Arch 436:257–270 Scholz D, Ziegelhoeffer T, Helisch A et al (2002) Contribution of arteriogenesis and angiogenesis to postocclusive hindlimb perfusion in mice. J Mol Cell Cardiol 34:775–787 Simons M, Eichmann A (2015) Molecular controls of arterial morphogenesis. Circ Res 116:1712–1724 Stabile E (2003) Impaired arteriogenic response to acute hindlimb ischemia in CD4-knockout mice. Circulation 108:205–210 Stabile E (2005) CD8+ T lymphocytes regulate the arteriogenic response to ischemia by infiltrating the site of collateral vessel development and recruiting CD4+ mononuclear cells through the expression of Interleukin-16. Circulation 113:118–124

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Takeda Y, Costa S, Delamarre E et al (2011) Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 479:122–126 Topper JN, Gimbrone MA Jr (1999) Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype. Mol Med Today 5:40–46 Tronc F, Wassef M, Esposito B et al (1996) Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol 16:1256–1262 van Royen N, Piek JJ, Buschmann I et al (2001) Stimulation of arteriogenesis; A new concept for the treatment of arterial occlusive disease. Cardiovasc Res 49:543–553 van Weel V, Toes REM, Seghers L et al (2007) Natural killer cells and CD4+ T-cells modulate collateral artery development. Arterioscl Thromb Vasc Biol 27:2310–2318 Wolf C, Cai WJ, Vosschulte R et al (1998) Vascular remodeling and altered protein expression during growth of coronary collateral arteries. J Mol Cell Cardiol 30:2291–2305 Zheng W, Christensen LP, Tomanek RJ (2008) Differential effects of cyclic and static stretch on coronary microvascular endothelial cell receptors and vasculogenic/angiogenic responses. Am J Physiol Heart Circ Physiol 295:H794–H800 Ziegelhoeffer T (2004) Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res 94:230–238

Chapter 7

Mast Cells in Primary Systemic Vasculitides

7.1 Background Vasculitides are characterized by inflammation and necrosis of blood vessels leading to vessel occlusion and ischemic damages of tissues (Dammacco et al. 2016). The final result is myointimal proliferation, fibrosis and thrombus formation leading to stenosis or occlusion of the vascular lumen, and finally to vascular ischemia. Moreover, in these diseases the hypoxic environment subsequent to stenosis or occlusion of the vascular lumen is a potent signal for the generation of new blood vessels. Endothelial cell diversity has crucial implications for vascular diseases’ development. Systemic vasculitides target distinct segments and branches of the vascular tree as well as selective vascular beds, and thrombotic or haemorrhagic conditions recognize specific vascular beds as the sites of disease occurrence. Potential implications for the pathogenesis of vascular metabolic diseases like atherogenesis are also strong (Dammacco et al. 2016). Angiogenesis may be a compensatory response to ischemia and to the increased metabolic activity and may be also a further inflammatory stimulus because endothelial cells of newly-formed vessels express adhesion molecules and produce colony stimulating factors and chemokines for leukocytes (Maruotti et al. 2008). Vasculitides are classified on the basis of type of vessel involved (large, medium, or small) accordingly to 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (Table 7.1) (Jennette et al. 2013). Large vessel vasculitis, including giant cell arteritis (GCA) and Takayasu arteritis (TA) involves the aorta and its major branches. GCA is characterized by granulomatosus infiltrate that typically occurs in medium and large arteries with well-developed wall layers and adventitial vasa vasorum (Salvarani et al. 2008; Weyand and Goronzy 2014). GCA affects aorta, mainly the thoracic segment, and its extracranial branches including the external carotid, the ophthalmic, vertebral, distal subclavian, axillary, and rarely lower limb arteries. Rarely the inflammation of intracranial arteries occurs (Salvarani et al. 2008; Weyand and Goronzy 2014; Chatterjee et al. 2014; Chacko et al. 2015). The inflammatory cell infiltrate is constituted by activate macrophages, CD4 T cells © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_7

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and multinucleated giant cells; moreover, dendritic cells in adventitia-media border of the artery play an important role in the initiation of vasculitis. Indeed, it has demonstrated that active dendritic cell become chemokine-producing effector cells able of recruiting CD4 T lymphocytes and macrophages that are the main responsible in the sustaining the granulomatous inflammation in the arteries (Salvarani et al. 2008; Guida et al. 2014) In the affected vessels, inflammatory infiltrate constituted by neutrophils and eosinophils can also be found as well as also CD8 positive lymphocytes are involved Salvarani et al. 2008; Weyand and Goronzy 2014; Chatterjee et al. 2014; Gonzalez-Gay and Pina 2015). Takayasu arteritis (TA), it is a chronic, inflammatory systemic vasculitis that preferentially affects young women in their child-bearing age. TA involves principally large vessels, in particular the aorta and its main branches (the subclavian arteries in about 80% of patients, followed by the carotids, thoracoabdominal aorta, and celiac trunk). Inflammation can induce increased wall thickness with stenosis or occlusion of the lumen, while the impairment of the media can determine aneurysm formation in 10–25% of patients (Gatto et al. 2012; Fredi et al. 2015). Inflammatory infiltrate is most intense in proximity to vasa vasorum and includes macrophages, CD4 and CD8 positive T cells, γδ T cells, natural killer (NK) cells, dendritic cells and rare B-cells. Multinucleated giant cells can be present at the mediaintima border. Under lymphocyte drive, macrophages and the stromal components of the arterial wall would cause the injuries and the remodeling that are observed histologically and that are responsible for the clinical manifestations (Saadoun et al. 2015; Hoyer et al. 2012). Medium vessel vasculitides, including polyarteritis nodosa (PAN) and Kawasaki disease (KD), involves medium vessel arteries and their initial branches in the parenchyma. Kawasaki disease (KD) is one of the most common childhood vasculitides after Henoch-Schoenlein purpura, the main cause of acquired heart disease among children living in industrialized countries and an important cause of long-term cardiac disease in adult life (Kawasaki et al. 1974; Gardner-Medwin et al. 2002). Small vessel vasculitides involves capillaries, post-capillary venules and arterioles, and Small include: (i) immune complex-mediated diseases (cryoglobulinemic vasculitis, IgA vasculitis, hypocomplementemic urticarial vasculitis); (ii) anti-neutrophilic cytoplasmic antibody (ANCA)-associated forms (granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), renal limited vasculitis. Immunohistochemical analysis of infiltrating cell phenotypes has provided interesting information regarding pathogenetic mechanisms involved in vasculitides. Among the inflammatory cells involved in vasculitides, neutrophils, T cells and macrophages have been identified as the predominant cell type.

7.1 Background

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Table 7.1 Names for vasculitides adopted by the 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides Large vessel vasculitis (LVV)

Takayasu arteritis (TAK) Giant cell arteritis (GCA)

Medium vessel vasculitis (MVV)

Polyarteritis nodosa (PAN)

Small vessel vasculitis (SVV)

ANCA-associated vasculitis (AAV)

Kawasaki disease (KD) Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (Wegener’s) (GPA) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Immune complex vasculitis Anti-glomerular basement membrane (anti-GBM) disease Cryoglobulinemic vasculitis (CV) IgA vasculitis (Henoch-Scho¨nlein) (IgAV) Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis) Variable vessel vasculitis (VVV)

Behcet’s disease (BD)

Single-organ vasculitis (SOV)

Cutaneous leukocytoclastic angiitis

Cogan’s syndrome (CS Cutaneous arteritis Primary central nervous system vasculitis Isolated aortitis Others Vasculitis associated with systemic disease

Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis Others

Vasculitis associated with probable etiology

Hepatitis C virus-associated cryoglobulinemic vasculitis Hepatitis B virus-associated vasculitis Syphilis-associated aortitis Drug-associated immune complex vasculitis Drug-associated ANCA-associated vasculitis Cancer-associated vasculitis Others

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7.2 Experimental Evidence of the Involvement of Mast Cells in Vasculitides Around veins in which thrombosis was produced by sclerosing agents in rabbits, mast cell density increases (Pettersson and Hjelmman 1964). Mast cell deficient mice (Kit W−sh/W−sh ) are characterized by the presence of more anti-myeloperoxidase (MPO) CD4+ T cells, a stronger delayed hypersensitivity response to MPO, more severe glomerulonephritis, and fewer T cells compared to wild type mice (Gan et al. 2012). Reconstitution of mast cells from wild type control mice significantly increased the Treg numbers and attenuated the severity of the glomerulonephritis (Gan et al. 2012). Mast cells play a role in early vasculitis in the Brown Norway rat model of vasculitis, which is similar to eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) (Vinen et al. 2004). In this experimental model, administration of mercuric chloride (Hg2 Cl2 ) to brown Norway rats causes Th-2-dominated autoimmunity with raised IgE concentration and gut vasculitis. The authors of this study demonstrated a direct correlation between mast cell degranulation and early caecal vasculitis following Hg2 Cl2 challenge.

7.3 Clinical Evidence of the Involvement of Mast Cells in Vasculitides The presence of mast cells has been demonstrated in different vasculitides (Table 7.2). Battezzati (1951) found a large number of mast cells in the walls of arteries affected by thromboangiitis and Pomerance (1958) demonstrated that the number of mast cells around the coronary arteries is considerably increased in patients with coronary occlusion. GCA is the most common form of primary systemic vasculitis affecting aorta and its principal branches (Hunder 1997). It affects patients older than 50 years and is

Table 7.2 Involvement of mast cells in different vasculitides

Vasculitides

Mast cell localization

Tromboangitiis

Coronary artery

Giant cell arteritis (GCA)

Temporal artery

Necrotizing angitiis

Perivascular

Takayasu arteritis (TA)

Aorta

Kawasaki disease (KD)

Coronary artery

Behçet’s disease (BD)

Synovium

Autoimmune anti-MPO glomerulonephritis

Kidney

Eosinophilic coronary periarteritis

Coronary artery

7.3 Clinical Evidence of the Involvement of Mast Cells in Vasculitides

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associated to polymyalgia rheumatic in about half of subjects. The inflammatory infiltrate consists of lymphocytes, plasma cells, histiocytes and multinucleated giant cells (specialized fused cells derived by macrophages that accumulate in media-intima of arterial wall). Mäyränpää et al. (2008) demonstrated by immunohistochemistry that tryptase-cathepsin G and VEGF-positive mast cells are associated with CD3-positive T cells and CD31-CD34-positive vessels in neointima of temporal arteries affected and arteritis lesions and suggested a pro-angiogenic role of mast cells in this disease. Moreover, mast cells may participate in the remodeling of the affected arteries by regulating smooth muscle cells growth and death (Leskinen et al. 2006). Fukunaga (2005) described a case of juvenile temporal arteritis in which mast cells infiltrates were present in the subcutaneous tissue surrounding the artery. Soter et al. (1976) demonstrated in cutaneous necrotizing angitis perivascular mast cells in the superficial portions of the dermis exhibiting striking degrees of hypogranulation, while in the deep dermis mast cells were less granulated. In patients with CGA serum levels of IL-6 are significantly higher (Weyand et al. 2000). Mast cell granules as well as mast cell-derived proteases and histamine synergistically enhanced lipopolysaccharide (LPS) or TNF-α induced IL-6 production by endothelial cells (Chi et al. 2001; Jehle et al. 2000; Li et al. 1997). Degranulated mast cells have been described in the synovium samples of patients affected by PMR (Mayranpaa et al. 2008). As concerns TA, a significant increased number of mast cells has been observed in aorta lesions of both diseases as compared to non-inflammatory aorta controls (Desbois et al. 2017). KD is a form of medium to small vessel vasculitis which almost exclusively occurs in pediatric populations and young children and frequently affects the coronary arteries leading to coronary artery aneurysms and acute thrombosis (Fujiwara and Hamashima 1978). Kawasaki lesions are characterized by thinning of the vascular media, inflammation and destruction of the extracellular matrix in the internal elastic lamina and in the trilaminar structure of the vessel wall (Fujiwara and Hamashima 1978). Freeman et al. (2005) demonstrated the presence of tryptase-positive mast cells in KD coronary artery aneurysm adventitia and myocardium, and suggested that mast cell mediators, including NGF, VEGF and tryptase contribute to the angiogenic response occurring in KD. There is clear evidence that mast cells play an active and coordinate role in enhancing inflammatory and tumor angiogenesis, either directly through the release of angiogenic cytokines and proteolytic enzymes, or indirectly through paracrine signals. Cañete et al. (2009) investigated synovial inflammatory cells in early Behçet disease (BD) and psoriatic arthritis, demonstrated that the number of mast cells CD117 (c-Kit)-positive was lower in BD vs psoriatic arthritis even if there was no difference in the number of CD31-positive blood vessels.In kidney bioptic specimens form patients with autoimmune anti-MPO glomerulonephritis a higher number of interstitial degranulated mast cells was recognizable as compared with controls (Gan et al. 2015). Administration of disodium cromoglycate, a mast cell stabilizing agent, inhibited the development of experimental glomerulonephritis and mast cells presence within the kidney (Gan et al. 2015). A higher number adventitial mast cells are recognizable in the dissected portion of coronary arteries in the course of eosinophilic coronary periarteritis (Mandal et al. 2015).

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7.4 Therapeutic Perspectives Mast cells are characterized by their complex plasticity. Increasing evidences document that mast cells exert both pro-and anti-inflammatory functions depending on the cell types and the microenvironment they reside in. It is extremely difficult to establish the exact role played by mast cells in vasculitides, protective or promoters of the disease, or both. Probably, this depends by the interactions with other inflammatory cells involved in the pathogenesis of the disease and by the specific organ microenvironment in the different stages. Common treatment of vasculitides includes corticosteroids and cytotoxic drugs. Corticosteroids reduce inflammation in blood vessels. Cytotoxic drugs, including azathioprine, methotrexate, and cyclophosphamide, are used if corticosteroids don’t work well. Other more specific treatments may be used for certain types of vasculitis. For example, the standard treatment for KD is high-dose aspirin and immune globulin (Ebato et al. 2017). Therapeutic strategies may also include inhibition of recruitment of mast cells to the inflammatory infiltrate in vasculitis and blockade of proinflammatory effects and pro-angiogenic functions (Theoharides et al. 2012). Mast cell stabilizers, including gabexate mesilate and nafomostat mesilate, two inhibitors of trypsin-like serine protease, inhibit tryptase, an angiogenic factor stored in mast cell granules (Ribatti 2016). In the light of the present knowledge, mast cells might be regarded in a future perspective as a new target for the adjuvant treatment of vasculitides through the selective inhibition of angiogenesis, tissue remodeling and inflammatory-promoting molecules.

References Battezzati M (1951) Sur la Présence des Mastzellen Dans la Paroi des Artères et Dans la Moelle Osseuse Dans les Thromboangéites. Presse Méd 59:1628 Cañete JD, Celis R, Noordenbos T et al (2009) Distinct synovial immunopathology in Behçet disease and psoriatic arthritis. Arthritis Res Ther 11:R17 Chacko JG, Chacko JA, Salter MW (2015) Review of Giant cell arteritis. Saudi J Ophthalmol 29:48–52 Chatterjee S, Flamm SD, Tan CD et al (2014) Clinical diagnosis and management of large vessel vasculitis: giant cell arteritis. Curr Cardiol Rep 16:499 Chi L, Li Y, Stehno-Bittel L et al (2001) Interleukin-6 production by endothelial cells via stimulation of protease-activated receptors is amplified by endotoxin and tumor necrosis factor-α. J Interferon Cytokine Res 21:231–240 Dammacco F, Ribatti D, Vacca A (eds) (2016) Systemic vasculitides: current status and perspectives. Springer, Berlin Desbois A, Cacoub P, Leroyer A et al (2017) The critical role of interleukin-33 in promoting angiogenesis and regulates inflammation through mast cells in Takayasu arteritis. Paper presented at: American College of Rheumatology Annual Meeting Ebato T, Ogata S, Ogihara Y et al (2017) The clinical utility and safety of a new strategy for the treatment of refractory Kawasaki disease. J Pediatr 191:140–144

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Fredi M, Lazzaroni MG, Tani C et al (2015) Systemic vasculitis and pregnancy: a multicenter study on maternal and neonatal outcome of 65 prospectively followed pregnancies. Autoimmun Rev 14:686–691 Freeman AF, Crawford SE, Cornwall ML et al (2005) Angiogenesis in fatal acute Kawasaki disease coronary artery and myocardium. Pediatr Cardiol 26:578–584 Fujiwara H, Hamashima Y (1978) Pathology of the heart in Kawasaki disease. Pediatrics 61:100–107 Fukunaga M (2005) Juvenile temporal arteritis associated with Kimura’s disease. Case report. APMIS 113:379–384 Gan PY, Summers SA, Ooi JD et al (2012) Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis. J Am Soc Nephrol 23:1955–1966 Gan PY, Osullivan KM, Ooi JD et al (2015) Mast cell stabilization ameliorates autoimmune antimyeloperoxidase glomerulonephritis. J Am Soc Nephrol 27:1321–1333 Gardner-Medwin JM, Dolezalova P, Cummins C et al (2002) Incidence of Henoch-Schonlein Purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet 360:1197–1202 Gatto M, Iaccarino L, Canova M et al (2012) Pregnancy and vasculitis: a systematic review of the literature. Autoimmun Rev 11:A447–A459 Gonzalez-Gay MA, Pina T (2015) Giant cell arteritis and polymyalgia rheumatica: an update. Curr Rheumatol Rep 17:6 Guida A, Tufano A, Perna P et al (2014) The thromboembolic risk in giant cell arteritis: a critical review of the literature. Int J Rheumatol 2014:806402 Hoyer BF, Mumtaz IM, Loddenkemper K et al (2012) Takayasu arteritis is characterised by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab. Ann Rheum Dis 71:75–79 Hunder GG (1997) Giant cell arteritis and polymyalgia rheumatica. Med Clin North Am 81:195–219 Jehle AB, Li Y, Stechschulte AC et al (2000) Endotoxin and mast cell granule proteases synergistically activate human coronary artery endothelial cells to generate interleukin-6 and interleukin-8. J Interferon Cytokine Res 20:361–368 Jennette JC, Falk RJ, Bacon PA et al (2013) Revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 65:1–11 Kawasaki T, Kosaki F, Okawa S et al (1974) A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics 54:271–276 Leskinen M, Heikkila H, Speer M et al (2006) Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-Kb-mediated survival signaling. Exp Cell Res 312:1289–1298 Li Y, Stechschulte AC, Smith DD et al (1997) Mast cell granules potentiate endotoxin-induced interleukin-6 production by endothelial cells. J Leukoc Biol 62:210–216 Mandal R, Brooks EG, Corliss RF (2015) Eosinophilic coronary periarteritis with arterial dissection: the mast cell hypothesis. J Forensic Sci 60:1088–1092 Maruotti N, Cantatore FP, Nico B et al (2008) Angiogenesis in vasculitides. Clin Exp Rheumatol 26:476–483 Mayranpaa MI, Trosien JA, Nikkari ST et al (2008) Mast cells associate with T-cells and neointimal microvessels in giant cell arteritis. Clin Exp Rheumatol 26(3 Suppl 49):S63–S66 Pettersson T, Hjelmman G (1964) The effect of experimental venous thrombosis on the mast cells and fibrocytes in the vascular wall of the rabbit. Acta Med Scand 175(SUPPL 412):265 Pomerance A (1958) Peri-arterial mast cells in coronary atheroma and thrombosis. J Pathol Bacteriol 76:55–70 Ribatti D (2016) Mast cells as therapeutic target in cancer. Eur J Pharmacol 778:152–157 Saadoun D, Garrido M, Comarmond C et al (2015) Th1 and Th17 cytokines drive inflammation in Takayasu arteritis. Arthritis Rheumatol 67:1353–1360 Salvarani C, Cantini F, Hunder GG (2008) Polymyalgia rheumatica and giant-cell arteritis. Lancet 372:234–245 Soter NA, Mihm MC Jr, Gigli I et al (1976) Two distinct cellular patterns in cutaneous necrotizing angiitis. J Invest Dermatol 66:344–350

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Theoharides TC, Alysandratos KD, Angelidou A et al (2012) Mast cells and inflammation. Biochim Biophys Acta 1822(1):21–33 Vinen CS, Turner DR, Oliveira DB (2004) A central role for the mast cell in early phase vasculitis in the Brown Norway Rat model of vasculitis: a histological study. Int J Exp Pathol 85:165–174 Weyand CM, Goronzy JJ (2014) Clinical practice. Giant-cell arteritis and polymyalgia rheumatica. N Engl J Med 371:50–57 Weyand CM, Fulbright JW, Hunder GG et al (2000) Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 43:1041–1048

Chapter 8

Mast Cells in Blood-Brain Barrier Alterations and Neurodegenerative Diseases

8.1 The Blood-Brain Barrier The blood-brain barrier (BBB) is found in the brain all vertebrates and the presence of a barrier only in the invertebrates capable of complex central nervous system (CNS) functions might indicate that a barrier is needed when the level of integrative activity in the nervous tissues reaches a critical level. The seminal work of Reese and Karnovsky (1967) demonstrated for the first time that the barrier is a property of endothelial cells. Reese and Karnovsky showed for the first time at ultrastructural level that the endothelium of mouse cerebral capillaries constitutes a structural barrier to the macromolecular tracer horseradish peroxidase (HRP). This barrier is composed of the plasma membrane and the cell body of endothelial and of tight junctions between adjacent cells. The tight junctions completely obliterate the narrow cleft between adjacent cells forming a continuous belts or rows of zonulae occludentes. Reese and Karnovsky (1967) found that HRP was able to enter in the interendothelial spaces only up, but not beyond, the interendothelial tight junctions. Microscopic examination of the brain microvasculature shows that the endfeet of astrocytic glia are closely apposed to the outer surface of the endothelium, leading to the suggestion that inductive influences from astrocytic glia could be responsible for the development of the BBB phenotype of the brain endothelium (Wolburg et al. 1994). Many of the factors released by astrocytes are able to induce specific features of the BBB in brain endothelium. When placed in culture CNS microvessels rapidly lose their barrier characteristics, which can be partially restored by co-culturing with astrocytes (Wolburg et al. 1994). Through long cytoplasmic processes, pericytes make focal contacts with brain endothelial cells through communicating gap junctions, tight junctions and adherens junctions. Immunocytochemical studies have shown the existence of BBBspecific enzymes in pericytes, e.g. gamma-glutamyltranspeptidase (Risau et al. 1992). A decrease in pericyte coverage directly correlates with reduced barrier characteristics of CNS microvessels. Daneman et al. (2010) and Armulik et al. (2010) used genetic mouse models with defects in pericyte generation and localization to © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_8

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demonstrate that pericyte-endothelial cell interactions are critical for BBB regulation during development and maintenance. The BBB functions to protect the brain from unwanted blood born materials, support unique metabolic needs of the brain, and defines a stable environment crucial for brain homeostasis. BBB breakdown has been associated with the initiation and perpetuation of various neurological disorders, including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and brain tumors (Zlokovic 2008).

8.2 Mast Cells in the Brain Several autocrine stimulators and inhibitors of mast cells have been indentified within the CNS. In the brain, mast cells are apposed to astrocytes in the perivasculature and when mast cells and astrocytes are co-cultured, mast cells are stimulated to release histamine, leukotriens and cytokines, via the activation of CD40-CD40 ligand (CD40L) interactions (Kim et al. 2010, 2011). Moreover, astrocytes express histamine receptors (Hosli et al. 1984) and release cytokines that are capable of inducing mast cell degranulation (Dong and Benveniste 2001). Pathogen Associated Molecular Patterns (PAMPs and ATP) activate glia to produce interleukin-33 (IL-33) and IL-1β eliciting the production of large amounts of inflammatory cytokines by mast cells (Bulanova and Bulfone-Paus 2010). IL-13 expresses by mast cells activates glia to produce other pro-inflammatory molecules including arginase, IL-6, monocyte chemotactic protein-1 (MCP-1), and TNF-α (Kim et al. 2010; Hudson et al. 2008). Intramuscular injection of mast cell degranulator compound 48/80 results in vastly increased Evans blue trace leakage in mast cell rich brain regions bearing fenestrated capillaries. Mast cell effects on vascular permeability are blocked by mast cell stabilizers and are absent in mast cell-deficient W/Wv mice (Theoharides et al. 2005). In vitro, mast cell protease degrade myelin protein and myelin directly stimulates mast cell degranulation (Brenner et al. 1994; Dietsch and Hinrichis 1991; Johnson et al. 1988). Mast cells are critical regulators in the pathogenesis of CNS diseases, including stroke, multiple sclerosis, and traumatic brain injury, all associated with various degree of inflammation, and brain tumors in which there is an alteration of the BBB (Lindsberg et al. 2010; Strbian et al. 2009).

8.3 Mast Cells in Cerebral Ischemia In cerebral ischemia mast cells act on the abluminal side of the neurovascular unit inducing BBB opening, brain edema, prolonged extravasation, hemorrhage and local inflammation (Lindsberg et al. 2010). Mast cells amplify and prolong the endothelial

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expression of adhesion molecules and the continued breakdown of the BBB thereby enabling the infiltration of other blood-borne cells and signals (Mattila et al. 2011). Stribian et al. (2007) injected freshly collected autologous arterial blood into the basal ganglia of the brain, and mast cell deficient rats responded with reduced brain swelling and hematoma growth compared to wild-type animals, and intravenous administration of cromoglycate was effective in reducing brain edema. Massive brain edema is the leading cause of death in large hemispheric strokes. Thrombolysis with tPA is the approved therapy in acute ischemic stroke within 4.5 h after symptom onset. Mattila et al. (2011) demonstrated that cerebral mast cells secreted gelatinasepositive granules participating in the regulation of acute microvascular gelatinase activation and BBB disruption following transient cerebral ischemia. Moreover, genetic mast cell deficiency and mast cell stabilization with cromoglycate decreased global gelatinase-active area and the mean-gelatinase activity of the ischemic microvasculature. Adult rats that underwent transient, middle cerebral artery occlusion (MCO) showed that mast cells are involved in ischemic brain edema shortly after focal cerebral ischemia onset (Strbian et al. 2006) and demonstrated an increase of almost 90% in edema after treatment with the mast cell-degranulating agent compound 48/80 and a reduction of nearly 40% in ischemic brain edema after treatment with the mast cell stabilizing agent sodium-cromoglycate.

8.4 Mast Cells in Multiple Sclerosis Mast cells were first observed in the CNS lesions of multiple sclerosis patients in 1890 (Neuman 1890). Microarray analysis of multiple sclerosis lesions shows that transcripts encoding tryptase, histamine, and Fc™RI are significantly increased in chronic disease (Bomprezzi et al. 2003; Lock et al. 2002). Elevated levels of tryptase are present in the cerebrospinal fluid of multiple sclerosis patients (Rozniecki et al. 1995), and can activate peripheral mononuclear cells to secrete TNFα, IL-6 and IL1b (Malamud et al. 2003) as well as stimulate protease activated receptors (PARs), that can lead to microvascular leakage and widespread inflammation (Bunnett 2006). Experimental autoimmune encephalomyelitis (EAE) corresponds to the murine model of multiple sclerosis induced in genetically susceptible rodents upon immunization with myelin peptide [myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG)] in complete Freund’s adjuvant (Steinman and Zamvil 2005). Both EAE and multiple sclerosis progress in a stagewise manner including initial activation of na¨ιve myelin-specific autoreactive T cells in peripheral lymphoid organs, followed their traffic to the CNS, which is facilitated by an opening of the BBB (Sospedra and Martin 2005). In EAE, meningeal mast cells promote cellular influx into the CNS by altering BBB integrity through expression of TNF-α, which recruits neutrophils and leads to increased permeability. The entry of neutrophils into the meninges and the CNS

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parenchyma was abrogated in the absence of mast cells-derived TNF-α (Sayed et al. 2010; Secor et al. 2000). Moreover, mast cells influence Th1 differentiation in vivo in a murine model of EAE (Gregory et al. 2006; Kampuraj et al. 2008; Gregory et al. 2005). Rats and mice with EAE exhibit increased degranulation of their brain mast cells (Kim et al. 2010) and elevated levels of the demyelinating mast cell protease (Rouleau et al. 1997). Increased number of mast cells and their activation products are detected in the brain and spinal cord of multiple sclerosis patients and mice with EAE (Sayed et al. 2008). Mast cell-deficient W/Wv mice displayed onset and reduced severity of EAE compared to their wild type littermates (Secor et al. 2000). Reconstitution of the mast cell compartment restores disease severity-despite the failure to repopulate mast cell within the parenchyma of the CNS suggesting that mast cells can exert their pathogenetic effects in the periphery (Tanzola et al. 2003). Moreover, mast cell deficient W/Wv mice displayed significantly reduced levels of primary progressive EAE symptom logy compared with controls, using a myelin oligodendrocyte glycoprotein (MOG)-induced model of EAE. This was abrogated following reconstitution of the mast cell population. Sayed et al. (2011) have developed a model of mast cell deficient SJL to study the role of mast cells in relapsing remitting disease and observed a reduced autoreactive T cell response which was restored and associated with normal T cell activity following mast cells reconstitution. Literature data have shown discrepancies derived by the use of different mouse strains (Rodewald and Feyerabend 2012). It is important to take in account differences in findings between distinct mast cell-deficient mouse models as well as those between different laboratories. To avoid this risk, systematic analysis of different parameters, such as sex and age of the animals, different immunization protocols should be performed. Finally, experimental data obtained in mouse experimental systems are not applicable to humans, because in human pathological conditions in which mast cells are completely lacking have not been reported. The severity of EAE can be reduced by preventing activation of mast cells by administration of the mast cell stabilizer picroximil, the H1 receptor antagonist hydroxyzine, or intracisternal administration of C48/80 before immunization (Brown and Hatfiled, 2012; Dimitriadou et al. 2000), a serotonin receptor antagonist (cyproheptadine) or a depletory of vasoactive amines in mast cell granules (reserpine) (Dimitriadou et al. 2000; Dietsch and Hinrichs 1989).

8.5 Mast Cells in Angiogenesis Occurring in Disease Associated with Blood-Brain Barrier Alterations Increased angiogenesis is a common feature of stroke, multiple sclerosis, and brain tumors (Greenberg and Jin 2005; Holley et al. 2010). An elevated VEGF expression was detected in reactive astrocytes of both active and inactive chronic demyelinated lesions (Proescholdt et al. 2002), in normal-appearing white matter from postmortem

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Fig. 8.1 12-day-old chick embryo CAMs incubated on day 8 for 4 days with gelatin sponges loaded with different cerebrospinal fluid (CSF) samples and 50 ng vascular endothelial growth factor (VEGF) used as positive control. Note that samples from relapsing–remitting (RR), secondary progressive (SP) and primary progressive (PP) patients induce a strong angiogenic response, in form of new-forming blood vessels radially converging toward the gelatin sponges, comparable to the angiogenic response induced by VEGF, while samples from neurological control (NC) and clinical isolated syndrome (CIS) induce a lower angiogenic response. Reproduced from Ribatti et al. (2016)

multiple sclerosis brains (Graumann et al. 2003), and in sera of multiple sclerosis patients during clinical relapses (Tham et al. 2006). We have recently investigated the angiogenic activity of cerebrospinal fluid samples from multiple sclerosis patients with different stages of disease by means of the chick chorioallantoic membrane (CAM), and we have demonstrated for the first time that cerebrospinal fluid from patients affected by multiple sclerosis, since from the early stages of the disease, has a high angiogenic activity in the CAM assay (Fig. 8.1). Moreover, we found that this activity correlates with a progressive disease course (Ribatti et al. 2016).

8.6 Perspectives Mast cells might be regarded in a future perspective as a new target for the adjuvant treatment of neurodegenerative diseases and brain tumors through the selective inhibition of angiogenesis, tissue remodelling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression. The development of new mast cell-deficient mice might help to more correctly analyze mast cell functions and distinguish them from other mechanisms resulting from mast cell-independent c-kit effect or cre toxicity (the two mast cell-deficient mice models more utilized are characterized by an abnormal expression of the c-kit

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gene and by the expression of cre recombinase under the control of mast cell-specific gene promoters). Pharmacological inhibition and genetic deficiency of mast cells led to a significant reduction in post-ischemic BBB disruption, cerebral edema and neutrophil infiltration, suggesting that mast cell inhibition may be used as a potential therapeutic target to prevent inflammatory damage to the neurovasculature. Moreover, mast cells might be regarded in a future perspective as a new target for the adjuvant treatment of brain tumors through the selective inhibition of angiogenesis, tissue remodelling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression.

References Armulik A, Genove G, Mae M et al (2010) Pericytes regulate the blood-brain barrier. Nature 468:557–561 Bomprezzi R, Ringnér M, Kim S et al (2003) Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum Mol Gen 12:2191–2199 Brenner T, Soffer D, Shalit M et al (1994) Mast cells in experimental allergic encephalomyelitis: characterization, distribution in the CNS and in vitro activation by myelin basic protein and neuropeptides. J Neurol Sci 122:210–213 Brown MA, Hatfield JK (2012) Mast Cells are important modifiers of autoimmune disease: with so much evidence, why is there still controversy? Front Immunol 3:147 Bulanova E, Bulfone-Paus S (2010) P2 receptor-mediated signaling in mast cell biology. Purinergic Signal 6:3–17 Bunnett NW (2006) Protease-activated receptors: how proteases signal to cells to cause inflammation and pain. Sem Thromb Hemost 32:39–48 Daneman R, Zhou L, Kebede AA et al (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468:562–566 Dietsch GN, Hinrichs DJ (1989) The role of mast cells in the elicitation of experimental allergic encephalomyelitis. J Immunol 142:1476–1481 Dietsch GN, Hinrichs DJ (1991) Mast cell proteases liberate stable encephalitogenic fragments from intact myelin. Cell Immunol 135:541–548 Dimitriadou V, Pang X, Theoharides TC (2000) Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation. Int J Immunopharmacol 22:673–684 Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190 Graumann U, Reynolds R, Steck AJ et al (2003) Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol 13:554–573 Greenberg DA, Jin K (2005) From angiogenesis to neuropathology. Nature 438:954–959 Gregory GD, Robbie-Ryan M, Secor VH et al (2005) Mast cells are required for optimal autoreactive T cell responses in a murine model of multiple sclerosis. Eur J Immunol 35:3478–3486 Gregory GD, Raju SS, Winandry S et al (2006) Mast cell IL-4 expression is regulated by ikaros and influences encephalitogenic TH 1 responses in mice. J Clin Invest 116:1327–1336 Holley JE, Newcombe J, Whatmore JL et al (2010) Increased blood vessel density and endothelial cell proliferation in multiple sclerosis cerebral white matter. Neurosci Lett 470:65–70 Hösli L, Hösli E, Schneider U et al (1984) Evidence for the existence of histamine H1- and H2 receptors on astrocytes of cultured rat central nervous system. Neurosci Lett 48:287–291

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Hudson CA, Christophi GP, Gruber RC et al (2008) Induction of IL-33 expression and activity in central nervous system glia. J Leukoc Biol 84:631–643 Johnson D, Seeldrayers PA, Weiner HL (1988) The role of mast cells in demyelination. 1. Myelin proteins are degraded by mast cell proteases and myelin basic protein and P2 can stimulate mast cell degranulation. Brain Res 444:195–198 Kempuraj D, Tagen M, Iliopoulou BP et al (2008) Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell-dependent stimulation of Jurkat T cells. Br J Pharmacol 155:1076–1084 Kim DY, Jeoung D, Ro JY (2010) Signaling pathways in the activation of mast cells cocultured with astrocytes and colocalization of both cells in experimental allergic encephalomyelitis. J Immunol 185:273–283 Kim DY, Hong GU, Ro JY (2011) Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L. J Neuroinflammation 8: 25 Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML (2010) Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. J Cereb Blood Flow Metab 30:689–702 Lock C, Hermans G, Pedotti R et al (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500–508 Malamud V, Vaaknin A, Abramsky O et al (2003) Tryptase activates peripheral blood mononuclear cells causing the synthesis and release of TNF-alpha, IL-6 and IL-1 beta: possible relevance to multiple sclerosis. J Neuroimmunol 138:115–122 Mattila OS, Strbian D, Saksi J et al (2011) Cerebral mast cells mediate blood-brain barrier disruption in acute experimental ischemic stroke through perivascular gelatinase activation. Stroke 42:3600–3605 Neuman J (1890) Ueber das Vorkommen der Sogneannten “Mastzellen” bei Pathologischen Veraenderungen des Gehirns. Virchows Arch Pathol Anat Physiol 122:378–381 Proescholdt MA, Jacobson S, Tresser N et al (2002) Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats. J Neuropathol Exp Neurol 61:914–925 Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217 Ribatti D, Iaffaldano P, Marinaccio C et al (2016) First evidence of in vivo pro-angiogenic activity of cerebrospinal fluid samples from multiple sclerosis patients. Clin Exp Med 16:103–107 Risau W, Dingler A, Albrecht U et al (1992) Blood-brain barrier pericytes are the main source of gamma-glutamyltranspeptidase activity in brain capillaries. J Neurochem 58:667–672 Rodewald HR, Feyerabend TB (2012) widesperad immunological functions of mast cells: fact or fiction? Immunity 37:13–24 Rouleau A, Dimitriadou V, Trung Tuong MD et al (1997) Mast cell specific proteases in rat brain: changes in rats with experimental allergic encephalomyelitis. J Neural Transm 104:399–417 Rozniecki JJ, Hauser SL, Stein M et al (1995) Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann Neurol 37:63–66 Sayed BA, Christy A, Quirion MR et al (2008) The master switch: the role of mast cells in autoimmunity and tolerance. Annu Rev Immunol 26:705–739 Sayed BA, Christy AL, Walker ME et al (2010) Meningeal mast cells affect early t cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment? J Immunol 184:6891–6900 Sayed BA, Walker ME, Brown MA (2011) Cutting edge: mast cells regulate disease severity in a relapsing-remitting model of multiple sclerosis. J Immunol 186:3294–3298 Secor VH, Secor WE, Gutekunst CA et al (2000) Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J Exp Med 191:813–822 Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747 Steinman L, Zamvil SS (2005) Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol 26:565–571

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Strbian D, Karjalainen-Lindsberg ML, Tatlisumak T et al (2006) Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation. J Cereb Blood Flow Metab 26:605–612 Strbian D, Tatlisumak T, Ramadan UA et al (2007) Mast cell blocking reduces brain edema and hematoma volume and improves outcome after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 27:795–802 Strbian D, Kovanen PT, Karjalainen-Lindsberg ML et al (2009) An emerging role of mast cells in cerebral ischemia and hemorrhage. Ann Med 41:438–450 Tanzola MB, Robbie-Ryan M, Gutekunst CA et al (2003) Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course. J Immunol 171:4385–4391 Tham E, Gielen AW, Khademi M et al (2006) Decreased expression of VEGF-A in rat experimental autoimmune encephalomyelitis and in cerebrospinal fluid mononuclear cells from patients with multiple sclerosis. Scand J Immunol 64:609–622 Theoharides TC, Donelan J, Kandere-Grzybowska K et al (2005) The role of mast cells in migraine pathophysiology. Brain Res Brain Res Rev 49:65–76 Wolburg H, Neuhaus J, Kniesel U et al (1994) Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes. J Cell Sci 107:1347–1357 Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201

Chapter 9

Mast Cells and Basophils: A Link Between Angiogenesis and Inflammation in Allergic Diseases

9.1 General Biology and Mediators of Mast Cells and Basophils The main histochemical difference between mast cells and basophils is their distinct metachromatic staining, which primarily reflects their different content of proteoglycans of cytoplasmic granules. For instance, chondroitin sulfates is present both in basophils and mast cells whereas heparin is detectable in mast cells exclusively (Dvorak 2005). Mast cells and basophils have different developmental patterns. Mast cells are tissue-resident cells, which arise in the bone marrow from CD34+ haematopoietic stem cells (Okayama and Kawakami 2006). Basophils are circulating granulocytes that typically mature in the bone marrow, circulate in the blood as mature cells, and can be recruited into sites of immunological or inflammatory responses but are not found in normal tissues (Arock et al. 2002). They also arise from CD34+ haematopoietic progenitors and, under physiological conditions, have a short life-span of several days. Unlike mast cells, they do not proliferate once they mature. As basophils lack c-kit, they do not respond to SCF. By contrast, their differentiation is crucially driven by IL-3, which promotes the production and survival of human basophils in vitro and can induce basophilia in vivo (Valent et al. 1989). It is possible that human basophils and mast cells share a common precursor cell that expresses CD34, IL-3Rα and CD203c (also known as ENPP3) (Buhrinh et al. 2004). Like other granulocytes, basophils differentiate in the bone marrow, whereas mast cells enter peripheral tissues as immature cells (Kitamura et al. 1979). Basophils have a relatively short life span of about 60 h (Ohnmacht and Voehringer 2009), whereas mast cells survive for weeks to months (Kierman 1979). Major mediators stored preformed in mast cell granules are histamine, heparin, serine proteases such as tryptase and chymase, cathepsin G, peroxidase, many acidic hydrolases, carboxypeptidases and antimicrobial peptides such as cathelicidins (Galli et al. 2005a, b). Human and mouse mast cells secrete several C-C and CXC chemokines, including monocyte chemotactic protein (MCP)-1 (CCL-2) © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_9

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and macrophage inflammatory protein (MIP)-1α (CCL-3). Basophil granules contain less amount of histamine, lack heparin but contain proteoglycans like chondroitin sulphates and Charcot-Leyden crystal protein. In some allergic settings, circulating basophils may contain tryptase, chymase, carboxypeptidase A, and express the c-kit receptor—that normally lacks on the basophils surface—which suggests that these cells may modulate their phenotype (Li et al. 1998). Newly generated mediators consist of arachidonic acid metabolites, principally cysteinyl leukotrienes (LTB4 and LTC4 ), prostaglandins (PGE2 and PGD2 ), and platelet-activating factor (PAF) and cytokines such as TNF-α, TNF-β, TGF-β, FGF-2, VEGF, GM-CSF, NGF, PDGF, interferon alpha, beta, and gamma (IFN-α, -β and -γ), and IL-4, IL-5, IL-6, IL-1β, IL-13. By contrast, LTC4 and PAF are the only identified lipid mediators released by basophils (Karasuyama et al. 2009; Nouri-Aria et al. 2001; Schroeder et al. 2001). These mediators can exert profound effects on inflammation, immunity, haematopoiesis, tissue remodelling and other biological functions. L-8 (CXCL-8) has chemokine functions as well.

9.2 Mast Cells and Basophils in Allergy Both mast cells and basophils express the tetrameric αβγ2 form of the high-affinity receptor FcεRI for IgE on their surface and both kinds of cells are crucial effectors in T helper 2 (Th2)-cell-dependent, IgE-associated allergic disorders and immune responses to parasites (Gould et al. 2003; Prussin and Metcalfe 2003; Min et al. 2004). IgE play a crucial role in the immediate hypersensitivity response but other IgEindependent mechanisms, such as G protein-coupled receptor and Toll-like receptor activation processes may intervene (Marshall et al. 2003; Vines and Prossnitz 2004). Activated mast cells and basophils release Th2 cytokines (IL-4, IL-5, IL-9 and IL-13) that polarize the immune reaction, and produce various bioactive chemical mediators, such as histamine and lipid metabolites, that provide vasoactive, chemotactic and immunoregulatory functions (Schroeder et al. 2001; Min and Paul 2008). In addition to their roles in classic acute IgE-associated immediate hypersensitivity responses, mast cells and basophils can also contribute to late-phase and chronic allergic reactions (Galli et al. 2008a, b; Holgate 2002; Mukai et al. 2005). A key molecule in this context is IL-33 and the IL-33 receptor (IL-33R), a heterodimer comprised of IL-1RL1 and IL-1 receptor accessory protein (IL-1RAcP). Genetic polymorphism of IL-33 and IL-1RL1 is suspected of causing susceptibility to development of asthma in certain patients. Genetic polymorphism of IL-1RL1 has also been identified in patients with atopic dermatitis, and expression of IL-33 is increased in inflamed skin from these patients, suggesting involvement of IL33 in the development of atopic dermatitis. Human peripheral blood or cord blood progenitor cell-derived mast cells and mouse peritoneal and bone marrow-derived cultured mast cells constitutively express IL-1RL1 that induces expression of mouse mast cell protease-6, prolong survival and promote adhesion of naïve human and murine mast cells without inducing degranulation in response to IL-33. IL-33 can

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enhance IgE/Ag-, monomeric IgE-, C5a-, SCF- and NGF-mediated cytokine production in human and mouse mast cells. In human and/or mouse naïve basophils that constitutively express IL-1RL1, IL-33 can induce production of such cytokines and chemokines as IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF, CCL2, CCL3 and CCL4 and cell adhesion by promoting CD11b expression, without inducing degranulation or migration. IL-33 enhances IgE-mediated degranulation and migration as well as IgE- and IL-3-mediated cytokine and chemokine production in human and mouse basophils. IL-33 also enhances the receptor for leptin on human basophils, suggesting that IL-33 may be involved in metabolic abnormalities associated with inflammation via basophil activation. In ragweed pollen-induced allergic rhinitis, IL-33 enhances release of histamine and chemoattractant factors for eosinophils and basophils by mast cells and basophils, contributing to local inflammation in the early and late phases of diseases. IL-33 can induce production of chemokines such as CCL2, CCL3 and CCL4 by human and mouse naïve basophils that constitutively express IL-1RL1. Thus, not only CXC chemokines are responsible for leukocyte recruitment to inflamed tissues but they also regulate the inflammatory reaction leading to angiogenesis, tissue repair and new tissue generation (Romagnani et al. 2004). Another proinflammatory cytokine recently found to be involved in allergy is IL-18. IL-18 plays an important role in Th1/Tc1 polarization and promoting the production of Th2 cytokines (e.g., IL-4, IL-5, IL-9, and IL-13) by T cells, NK cells, basophils, and mast cells. IL-18 can act as a cofactor for Th2 cell development and IgE production, and also plays an important role in the differentiation of Th17 cells. IL-18 is a key player in the pathogenesis of inflammatory diseases such as atopic dermatitis, and plays a key role in the pathogenesis of pulmonary inflammatory diseases, including bronchial asthma and chronic obstructive pulmonary disease. In asthmatics, the number of the mast cells increases at sites of inflammation. Activation of mast cells is detected by higher spontaneous release of histamine by mast cells obtained from the bronchoalveolar lavage (BAL) of asthmatics and by elevated levels of tryptase and PGD2 in BAL. Mast cells change their degranulation pattern from acute to chronic allergic responses (Theoharides et al. 2007). Many clinical symptoms of IgE-dependent late-phase reactions, both in the respiratory tract, gastrostrointestinal tract and the skin, reflect the actions of the leukocytes recruited to these sites by mast cells and basophils through release of TNF-α, IL-6, IL-8, neutral proteases, as well as histamine and lipid mediators (Puxeddu et al. 2005). The development of allergic rhinitis proceeded in two distinct stages: histamine release from FcεRI-activated mast cells, followed by histamine-mediated recruitment of H(4)R-expressing basophils to the nasal cavity and activation through FcεRI (Shiraishi et al. 2013). Certain mast cell cytokines, including TNF-α, VEGF, FGF-2 and TGF-β, contribute to chronic allergic inflammation through effects on fibroblasts, vascular endothelial cells, and other cells resident at the sites of these reactions. Persistent chronic allergic inflammation can result in remodelling of the affected tissues and these structural changes are often associated with activation of the angiogenic process.

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9.3 Mast Cells and Basophils in Inflammation, Angiogenesis and Tissue Remodelling Airway tissues from patients with asthma characteristically show blood vessel proliferation in the mucosa and submucosa. The major structural and functional changes of the airway microcirculation include the proliferation of new vessels, increased vascular area of the medium and small airways, increased blood flow and microvascular permeability, and edema formation in the airway wall (Mc Donald 2001). Inflammation and angiogenesis are driven by numerous factors among which cytokines of the CXC family provide a pivotal role (Romagnani et al. 2004). Mast cells and basophils participate in the same inflammatory scenario along with other blood-born and tissue-resident cells in the course of different allergic conditions (Marone et al. 2005a), and cooperate in expanding and/or modulating inflammation as well as in mediating tissue remodelling and angiogenesis (Marone et al. 2005b). Mast cells and basophils are endowed with a wide set of chemokine receptors, and basophils constitutively express CCR1, CCR2, CCR3, CXCR1, CXCR3, and CXCR4 (Gibbs 2005). CCR3 is highly expressed on human basophils and can be activated by eotaxin (CCL11), RANTES (CCL5), MCP-3 (CCL7) and MCP-4 (CCL13) (Min et al. 2006). CCR3 is also expressed by about 25% of lung mast cells in subjects with bronchial asthma (Brightling et al. 2005). Upon IgE overproduction, mouse basophils release CCL22, which is a potent chemoattractant for Th2 cells and has been implicated in Th2-predominant allergic inflammation (Watanabe et al. 2008). Mast cells and basophils are a major source of several angiogenic factors among which VEGF. VEGF may be released by mast cells by exocytosis or in the absence of degranulation. Selective release of VEGF by human mast cells is mediated by CRH or by activation of the EP(2) receptor by PGE2 (Abdel-Majid and Marshall 2004; Cao et al. 2006). VEGF is also produced by human basophils (de Paulis et al. 2006), which express VEGF receptor-2 (VEGFR-2). VEGF-A also functions as basophil chemoattractant providing a novel autocrine loop for basophils self-recruitment. Both mast cells and basophils release histamine, which displays angiogenic activity in several in vitro and in vivo settings (Norrby 2002). Mast cells synthesize and release other potent angiogenic cytokines, such as FGF-2, the serine proteases tryptase and chymase, IL-8, TGF-β, TNF-α and NGF. In addition, both mast cells and basophils express the high affinity urokinase plasminogen activator receptor (uPAR) for the urokinase plasminogen activator (uPA) (Sillaber et al. 1997; de Paulis et al. 2004). uPA is a potent chemoattractant for both kind of cells and, remarkably, uPA and uPAR are involved in tissue remodelling and vessel sprouting. Human skin, lung and synovial mast cells contain matrix MMP-9, which degrade and remodel the ECM thus releasing ECM-bound angiogenic factors (Kanbe et al. 1999).

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References Abdel-Majid RM, Marshall JS (2004) Prostaglandin E2 induces degranulation-independent production of vascular endothelial growth factor by human mast cells. J Immunol 172:1227–1236 Arock M, Schneider E, Boissan M et al (2002) Differentiation of human basophils: an overview of recent advances and pending questions. J Leukoc Biol 71:557–564 Brightling CE, Kaur D, Berger P et al (2005) Differential expression of CCR3 and CXCR3 by human lung and bone marrow-derived mast cells: implications for tissue mast cell migration. J Leukoc Biol 77:759–766 Buhrinh HJ, Steble A, Valent P (2004) The basophil specific ectoenzyme E-NPP3 (CD203c) as a marker for cell activation and allergy diagnosis. Int Arch Allergy Immunol 133:317–329 Cao L, Curtis CL, Theoharides TC (2006) Corticotropin-releasing hormone induces vascular endothelial growth factor release from human mast cells via the cAMP/protein kinase A/P38 mitogen activate protein kinase pathway. Mol Pharmacol 69:998–1006 de Paulis A, Montuori N, Prevete N et al (2004) Urokinase induces basophil chemotaxis through a urokinase receptor epitope that is an endogenous ligand for formyl peptide receptor-like 1 and -like 2. J Immunol 173:7734–7743 de Paulis A, Prevete N, Rossi FW et al (2006) Expression and functions of vascular endothelial growth factors and their receptors in human basophils. J Immunol 177:7322–7331 Dvorak AM (2005) Ultrastructural studies of human basophils and mast cells. J Histochem Cytochem 53:1043–1070 Galli SJ, Kalesnikoff J, Grimbaldeston MA et al (2005a) Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 23:749–786 Galli SJ, Nakae S, Tsai M (2005b) Mast cells in the development of adaptive immune responses. Nat Immunol 6:135–142 Galli SJ, Grimbaldeston M, Tsai M (2008a) Immunomodulatory Mast Cells: Negative, as well as Positive, Regulators of Immunity. Nat Rev Immunol 8:478–486 Galli SJ, Tsai M, Piliponski AM (2008b) The Development of Allergic Inflammation. Nature 454:445–454 Gibbs BF (2005) Human basophils as effectors and immunomodulators of allergic inflammation and innate immunity. Clin Exp Med 5:43–49 Gould HJ, Sutton BJ, Beavil AJ et al (2003) The biology of IgE and the basis of allergic disease. Annu Rev Immunol 21:579–628 Holgate ST (2002) Airway inflammation and remodeling in asthma: current concepts. Mol Biotechnol 22:179–189 Kanbe N, Tanaka A, Kanbe M et al (1999) Human mast cells produce matrix metalloproteinase 9. Eur J Immunol 29:2645–2649 Karasuyama H, Mukai K, Tsujimura Y et al (2009) Newly discovered roles for basophils: a neglected minority gains new respect. Nat Rev Immunol 9:9–13 Kiernan JA (1979) Production and life span of cutaneous mast cells in young rats. J Anat 128:225–238 Kitamura Y, Hatanaka K, Murakami M et al (1979) Presence of mast cells precursors in peripheral blood of mice demonstrated by parabiosis. Blood 55:1085–1088 Li L, Li Y, Reddel SW et al (1998) Identification of basophilic cells that express mast cell granule proteases in the peripheral blood of asthma, allergy and drug-reactive patients. J Immunol 161:5079–5086 Marone G, Triggiani M, Genovese A et al (2005a) Role of human mast cells and basophils in bronchial asthma. Adv Immunol 88:97–160 Marone G, Triggiani M, de Paulis A (2005b) Mast cells and basophils: friends as well as foes in bronchial asthma? Trends Immunol 26:25–31 Marshall JS, McCurdy JD, Olynych T (2003) Toll-like receptor-mediated activation of mast cells: implications for allergic diseases? Int Arch Allergy Immunol 132:87–97

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Mc Donald DM (2001) Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am J Respir Crit Care Med 164:S39–S45 Min B, Paul WE (2008) Basophils and type 2 immunity. Curr Opin Hematol 15:59–63 Min B, Prout M, Hu-Li J et al (2004) Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J Exp Med 200:507–517 Min B, Le Gros G, Paul WE (2006) Basophils: a potential liaison between innate and adaptive immunity. Allergol Int 55:99–104 Mukai K, Matsuoka K, Taya C et al (2005) Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity 23:191–202 Norrby K (2002) Mast cells and angiogenesis. APMIS 110:355–371 Nouri-Aria KT, Irani AM, Jacobson MR et al (2001) Basophil recruitment and IL-4 production during human allergen-induced late asthma. J Allergy Clin Immunol 108:205–211 Ohnmatch C, Voehringer D (2009) Basophil effector function and homeostasis during helminth infection. Blood 113:2816–2825 Okayama Y, Kawakami T (2006) Development, migration and survival of mast cells. Immunol Res 34:97–115 Prussin C, Metcalfe DD (2003) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 111:S486–S494 Puxeddu I, Ribatti D, Crivellato E et al (2005) Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol 116:531–536 Romagnani P, Lasagni L, Annunziato F et al (2004) CXC Chemokines: the regulatory link between inflammation and angiogenesis. Trends Immunol 25:201–209 Schroeder JT, Lichtenstein LM, Roche EM et al (2001a) IL-4 production by human basophils found in the lung following segmental allergen challenge. J Allergy Clin Immunol 107:265–271 Schroeder JT, MacGlashan DW Jr, Lichtenstein LM (2001b) Human basophils: mediator release and cytokine production. Adv Immunol 77:93–122 Shiraishi Y, Jia Y, Domenico J et al (2013) Sequential engagement of Fcεri on mast cells and basophil histamine H(4) receptor and Fcεri in allergic rhinitis. J Immunol 190:539–548 Sillaber C, Baghestanian M, Hofbauer R et al (1997) Molecular and functional characterization of the urokinase receptor on human mast cells. J Biol Chem 272:7824–7832 Theoharides TC, Kempuraj D, Tagen M et al (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 217:65–78 Valent P, Schmidt G, Besemer J et al (1989) Interleukin-3 is a differentiation factor for human basophils. Blood 73:1763–1769 Vines CM, Prossnitz ER (2004) Mechanisms of G protein-coupled receptor-mediated degranulation. FEMS Microbiol Lett 236:1–6 Watanabe M, Satoh T, Yamamoto Y et al (2008) Overproduction of IgE induces macrophage-derived chemokine (CCL22) secretion from basophils. J Immunol 181:5653–5659

Chapter 10

Mast Cells in Tumor Fate

10.1 Tumor Microenvironment It is now well documented that neoplastic cells are influenced by their microenvironment and viceversa. The specific organ microenvironment determines the extent of cancer cell proliferation, angiogenesis, invasion and survival (Park et al. 2000; Liotta and Kohn 2001). These data indicate that a permissive stromal environment is important in supporting tumor progression in combination with genetic alterations. Tumor cells are surrounded by an infiltrate of inflammatory cells, namely lymphocytes, neutrophils, macrophages and mast cells, which communicate via a complex network of intercellular signaling pathways, mediated by surface adhesion molecules, cytokines and their receptors. The inflammatory cell infiltrate, particularly macrophages, may contribute to tumor angiogenesis, and there are many reports of associations between macrophage infiltration, vascularity and prognosis. Tumor-associated macrophages accumulate in poorly vascularized hypoxic or necrotic areas (Leek et al. 1999) and respond to experimental hypoxia by increasing the release of VEGF and FGF-2 and a broad range of other factors, such as TNF-α, FGF-2, VEGF, urokinase and matrix MMPs (Bingle et al. 2002). Moreover, activated macrophages synthesize and release inducible nitric oxide synthase (NOS), which increases blood flow and promotes angiogenesis (Jenkins et al. 1995). Lastly, the angiogenic factors secreted by macrophages stimulate mast cell migration (Gruber et al. 1995). The most aggressive human cancers, namely malignant melanoma, breast carcinoma, and colorectal adenocarcinoma, are associated with a dramatic host response composed of various inflammatory cells, especially mast cells at the tumor periphery. Mast cell infiltrate hyperplasias, dysplasias and invasive fronts of carcinomas (but not the core of solid tumors), where they degranulate in close apposition to capillaries and epithelial basement membranes.

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10.2 Mast Cells and Tumor Growth: Pros and Cons Mast cells accumulate at sites of tumor growth in response to numerous chemoattractants (Conti et al. 1997) and mediators (Table 10.1). Mast cells have a vast array of mediators, some of which have promoting, and others, inhibitory effects on malignancies (Tables 10.2 and 10.3) (Theodarides and Conti 2004). Secretion of cytokines from mast cells could occur without degranulation. This has been termed “differential release”, “intragranular activation”, or “piecemeal degranulation”, and may be associated with the ability of mast cells to release some mediators selectively without degranulation (Theoharides et al. 2007). Dabbous et al. (1986) showed that mast cell degranulation is associated with disruption and lysis of the tumor ECM either directly through the action of their enzymes, or indirectly through modulation of the collagenolytic activity of fibrob-

Table 10.1 Activators of mast cells in tumor microenvironment VEGF and Ang-1

Produced by tumor cells interact with VEGFR1/VEGFR2 and Tie2 expressed by mast cells

Hypoxia

Activates human mast cells to release IL-6 and VEGF-A

Adenosine

Potentiates histamine release and synthesis of angiogenic factors from mast cells

IL-33

Induces the production of GM-CSF, IL-8 and VEGF-A by mast cells

Table 10.2 Mast cell molecules involved in tumor initiation and progression Heparin Histamine

H1 receptor antagonists improve overall survival rates, suppress tumor growth, infiltration of mast cells and VEGF levels through inhibition of HIF-1α expression; dendritic cell maturation

ROS

Genetic instability; DNA and RNA damage; lipid peroxidation

VEGF-A, IL-8, FGF-2, PDGF

Angiogenesis

VEGF-C, VEGF-D

Lymphangiogenesis

NGF, MMP-9, uPA, uPAR, tryptase

Tissue remodeling and tumor invasiveness

IL-8, TGFβ

Epithelial mesenchymal transition

IL-8

Stemness

IL-6

Activation of STAT-3

Adenosine, TGFβ

Immunosuppression; adenosine potentiates histamine release and production of angiogenic factors from human mast cells

PAF

Proliferation of tumor cells

IL-13

Suppression of adaptive immunity; M2 polarization

Histamine

Tumor cell proliferation through H1 receptor and immune suppression through H2 receptor

IL-10, TNFα

Immunosuppression mediated by Treg cells

10.2 Mast Cells and Tumor Growth: Pros and Cons

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Table 10.3 Mast cell molecules involved in tumor regression ROS

Cytotoxicity

TNF-α

Cytotoxicity and leukocyte chemoattraction

Tryptase

Cytotoxicity and inflammation through activation of protease-activated receptor-1 and -2 (PAR-1 and PAR-2)

Heparin, IL-1, IL-4, IL-6

Inhibition of tumor cell growth and apoptosis

lasts, macrophages and tumor cells (Stack and Johnson 1994; Baram et al. 2001). Tryptase activates latent MMP and plasminogen activator, which, in turn, degrade the ECM (Stack and Johnson 1994). Mast cell chymase causes apoptosis in different target cells (Hara et al. 1999) and induces the accumulation of tumor associated macrophages, neutrophils and other inflammatory cells in vivo (He and Walls 1998). We have investigated the pattern of distribution of mast cells in biopsy samples obtained from four different human tumors, utilizing an image analysis system and a mathematical model to make a quantitative approach to characterizing their spatial distribution (Guidolin et al. 2008). In all tumors mast cells demonstrated a virtually random spatial distribution, albeit with varying densities, suggesting that mast cellmast cell interactions could play a minor role in the formation of the mast cell pattern in neoplastic tissues. The random distribution of the cells in the tissues could be accounted for by a random walk migration under the influence of cell-matrix interactions or chemotactic fields potentially generated by tumor or endothelial cells. Mast cells accumulate in high numbers in many human tumors exerting both detrimental and beneficial effects on tumor progression (Table 10.4). Tumors of mast cells are extremely rare, but certainly not as rare as commonly thought. The most common tumors of mast cells are those confined to the skin and manifests in childhood (Lennert and Parwaresch 1979). The group of the cutaneous mastocytosis consists of two types. The most common is designated urticaria pigmentosa and represents a disseminated involvement of the skin, while the localyzed type is made of solitary or multiple nodules and is called benign mastocytoma (Lennert and Parwaresh 1979). The clinical course in cutaneous mastocytosis is benign, in many cases, skin lesions disappear during puberty (Caplan 1963). Systemic mastocytosis is usually diagnosed in adulthood and is characterized by multiorgan involvement (with of without skin lesions) and disease peristence (Lennert and Parwaresh 1979). Indolent variants as well as aggressive variants of systemic mastocytosis have been reported (Lennert and Parwaresh 1979). Patients with systemic mastocytosis may be diagnosed with an associated clonal haematologic non-mast cell lineage disease (Travis et al. 1988) and mast cell-leukemia is a rare subtype of systemic mastocytosis defined by circulating mast cells and a rapidly deteriorating clinical course in most cases (Travis et al. 1988). Increased mast cell number has been correlated with a poor prognosis in oral squamous carcinoma (Iamaroon et al. 2003) and squamous cell carcinoma of the lip (Rojas et al. 2005).

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Table 10.4 Human tumors in which mast cells exert an anti-tumorigenic or pro-tumorigenic role Anti-tumorigenic

Breast cancer Melanoma Diffuse large B cell lymphoma Colorectal cancer Non-small cell lung cancer Mesothelioma Ovarian cancer Prostate Chronic myeloid leukemia

Pro-tumorigenic

Thyroid cancer Gastric cancer Colorectal cancer Hepatocellular carcinoma Pancreatic cancer Bladder cancer Prostate Merkel cell carcinoma Melanoma Endometrial cancer Breast cancer Cholangiocarcinoma Cutaneous lymphoma Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Myelodysplastic syndrome B-cell chronic lymphocytic leukemia Multiple myeloma Waldenstrom macroglobulinemia

Sharma et al. (1992) reported a higher number of mast cells in nodular sclerotictype Hodgkin’s lymphoma (HL) than in other types of HL and the number of mast cells was higher in fibrotic areas than in cellular areas. Molin et al. (2002, 2004) observed a worse prognosis for a nodular sclerosing HL exibiting a high mast cell number. Fukushima et al. (2006) demonstrated an increased number of tryptasepositive and chymase-positive mast cells in fibrotic areas in diffuse large B-cell lymphoma (DLCCL) lymph nodes. The greatest number of mast cells among T-cell lymphomas we observed in angioimmunoblastic T-cell lymphoma (Fukushima et al. 2001). Dave et al. (2004) utilized gene array to study the relationship between prognosis and a specific gene expression profile and concluded that the length of survival among patients with follicular lymphoma correlates with the molecular features of non-malignant immune cells present within the tumor at the time of diagnosis. One of the genes observed to correlate most negatively with survival was that of MITF, a transcription factor which has been found to be highly expressed in mast cells and to play a critical role in the regulation of several key mast cell-specific genes (Nechushtan and Razin 2002). Torunilhac et al. (2006) demonstrated that mast cells may support tumor cell expansion in Waldenstrom’s macroglobulinemia through consti-

10.2 Mast Cells and Tumor Growth: Pros and Cons

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tutive CD154-CD40 signaling. In detail, mast cells express CD154, a potent inducer of malignant B-cell proliferation, while bone marrow lymphoplasmacytic cells functionally expressed the CD154 receptor, CD40. Moreover, the use of CD154-CD40 signal inhibitor partially inhibited mast cell mediated bone marrow lymphoplasmacytic proliferation and/or tumor colony formation. Nonomura et al. (2007) demonstrated that in prostate cancer mast cell counts were higher around cancer foci in patients with higher Gleason scores that in those with low Gleason scores. Mast cell number correlated with clinical stage and multivariate analysis revealed that mast cell count was a significant prognostic factor. In brain tumors, mast cells accumulate in the stroma and are located at the BBB. They can release mediators such as histamine, IL-8, tryptase, and VEGF, disrupting the BBB (Theoharides et al. 2008). Mast cells infiltrate mouse and human gliomas, and the extent of mast cell infiltration is correlated with the malignancy grade of the tumor (Polajeva et al. 2011). Strong mast cell infiltration was detected in human glioma, where gliobastoma multiforme contained significantly higher mast cell numbers than grade II tumors did. Moreover, human glioblastoma multiforme was positive for chemokine (C-X-C motif) ligand-12 (CXCL-12) and the infiltrating mast cells were positive for CXC chemokine receptor-4 (CXCR-4) (Polajeva et al. 2011). In capillary hemangioblastoma mast cells are numerous in the tumor mass (Maslinska et al. 1999), and close association of mast cells with endothelial cells and stromal cells was found (Ho 1984). Mast cells as well as hypoxia are involved in meningioma progression, are associated with the formation of peritumoral brain edema, and may be useful markers in predicting the clinical course of meningioma (Reszec et al. 2013). Increased mast cell number has been correlated also with a good prognosis in several human tumors. Aaltomaa et al. (1993) found a positive correlation between survival and increased mast cell number in a study of 187 breast cancer biopsies. Dabiri et al. (2004) analyzed the correlation between mast cell number in breast cancer and patients’ prognosis in a study of 438 patients. They found a strong correlation between the presence of mast cells and a favorable prognosis. Perivascular tumorassociated mast cells in mammary adenocarcinoma could secrete several cytokines and proteolytic enzymes that could be detrimental to the tumor cells. For instance, IL-4, which binds to IL-4 receptors expressed by human breast carcinoma cells, could lead to apoptosis in breast cancer (Gooch et al. 1998). The histamine content of human breast cancer tissue is much higher than adjacent normal tissue and act as a local immunosuppressant (Ohno et al. 2002). Moreover, the mean level of serum tryptase in women with breast cancer is three-times higher than in healthy women (Samoszuk and Corwin 2003). Kankkunen et al. (1997) observed that significant increase in mast cell counts in breast carcinoma versus benign lesions is due to tryptase-containing mast cells. In benign lesions, the number of mast cells exhibiting tryptase activity was similar to that of chymase-active mast cells. Malignant tumors, however, had 2–3 times more tryptase-containing than chymase-containing mast cells, while the tryptase activity was significantly higher than in benign lesions. Moreover, in malignant lesions, tryptase-containing mast cells were concentrated at the tumor edge, whereas chymase-containing mast cells were not increased in this area. Breast cancer patients with metastases in the axillary nodes reveal greater num-

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bers of mast cells in all nodes examined compared with patients without metastasis (Thorense et al. 1982). Welsh et al. (2005) analyzed the presence of mast cells in the tumor stroma of 175 patients with surgical resected non small cell lung carcinoma and demonstrated that both macrophage and mast cell infiltration of the tumor islets was associated with a marked increase in 5-years survival, independently of other favorable prognostic factors including stage. Chan et al. (2005) studied samples of ovarian cancer from 44 patients and demonstrated that tumors with higher microvascular density had a higher mean survival compares with low mast cell density or low microvessel density.

References Aaltomaa S, Lipponen P, Papinaho S et al (1993) Mast cells in breast cancer. Anticancer Res 13:785–788 Baram D, Vaday G, Salamon P et al (2001) Human mast cells release metalloproteinase-9 on contact with activated T cells: juxtacrine regulation by TNF-alpha. J Immunol 167:4008–4016 Bingle L, Brown NJ, Lewis CE (2002) The role of tumor associated macrophages in tumor progression: implications for new anticancer therapies. J Pathol 196:254–265 Caplan RM (1963) The natural course of urticaria pigmentosa. Arch Dermatol 87:146–157 Chan JK, Magistris A, Loizzi V et al (2005) Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer. Gynecol Oncol 99:20–25 Conti P, Pang X, Boucher W et al (1997) Impact of rantes and MCP-1 chemokines on in vivo basohilic mast cell recruitment in rat skin injection model and their role in modifying the protein and mrna levels for histidine decarboxylase. Blood 89:4120–4127 Dabbous M, Walker R, Haney L et al (1986) Mast cells and matrix degradation at sites of tumor invasion in rat mammary adenocarcinoma. Br J Cancer 54:459–465 Dabiri S, Huntsman D, Makretsov N et al (2004) The presence of stromal mast cells identifies a subset of invasive breast cancers with a favorable prognosis. Mod Pathol 17:690–695 Dave SS, Wright G, Than B et al (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infilitrating immune cells. N Engl J Med 351:2159–2169 Fukushima N, Satoh T, Sano M et al (2001) Angiogenesis and mast cell in non hodgkin’s lymphoma; a strong correlation in angioimmunoblastic T-cell lymphoma. Leuk Lymphoma 42:709–720 Fukushima H, Ohsawa M, Ikura Y et al (2006) Mast cells in diffuse large B-cell lymphoma; their role in fibrosis. Histopathology 49:498–505 Gooch SJ, Lee AV, Yee D (1998) Interleukin 4 inhibits growth and induces apoptosis in human breast cancer cells. Cancer Res 58:4199–4205 Gruber BL, Marchese MJ, Kaw R (1995) Angiogenic factors stimulate mast cell migration. Blood 86:2488–2493 Guidolin D, Nico B, Crivellato E et al (2008) Tumoral mast cells exhibit a common spatial distribution. Cancer Lett 273:80–85 Hara M, Matsumori A, Ono K et al (1999) Mast cells cause apotosis of cardiomyocytes and proliferation of other intramyocardial cells in vitro. Circulation 100:1443–1449 He S, Walls AF (1998) Human mast cell chymase induces the accumulation of neutrophils, eosinophils and other inflammatory cells in vivo. Br J Pharmacol 125:1491–1500 Ho KL (1984) Ultrastructure of cerebellar capillary hemangioblastoma. II. Mast Cells and Angiogenesis. Acta Neuropathol 64:308–318 Iamaroon A, Pongsiriwet S, Jittidecharaks S et al (2003) Increase of mast cells and tumor angiogenesis in oral squamous cell carcinoma. J Oral Pathol Med 32:195–199

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Jenkins DC, Charles IG, Thompson LL et al (1995) Role of nitric oxide in tumor growth. Proc Natl Acad Sci USA 92:4392–4396 Kankkunen JP, Harvima IT, Naukkarinen A (1997) Qunatitative analysis of tryptase and chymase containing mast cells in benign and malignant breast lesions. Int J Cancer 72:385–388 Leek RD, Lander RJ, Harris AL et al (1999) Necrosis correlates with high vascular density and focal macrophages infiltration in invasive carcinoma of the breast. Br J Cancer 79:991–995 Lennert K, Parwaresch MR (1979) Mast cells and mast cell neoplasia: a review. Histopathology 3:349–365 Liotta L, Kohn EC (2001) The microenvironment of the tumor-host interface. Nature 411:375–379 Ma´sli´nska D, Wo´zniak R, Kaliszek A et al (1999) Phenotype of mast cells in the brain tumor. Capillary Hemangioblastoma. Folia Neuropathol 37:138–142 Molin D (2004) Bystander cells and prognosis in Hodgkin lymphoma. Review based on a doctoral thesis. Ups J Med Sci 109:179–228 Molin D, Edstrom A, Glimelius I et al (2002) Mast cell infilitration correlates with poor prognosis in hodgkin’s lymphoma. Br J Haematol 119:122–124 Nechushtan H, Razin E (2002) The function of MIFT and associated proteins in mast cells. Mol Immunol 38:1177–1180 Nonomura N, Takayama H, Nishimura K et al (2007) Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer. Br J Cancer 97:952–956 Ohno S, Inagawa H, Soma G et al (2002) Role of tumor-associated macrophage in malignant tumors: should the location of the infiltrated macrophages be taken into account during evaluation? Anticancer Res 22:4269–4275 Park CC, Bissell MJ, Barcellos-Hoff MH (2000) The influence of the microenvironment on the malignant phenotype. Mol Med Today 6:324–329 Polajeva J, Sjosten AM, Lager N et al (2011) Mast cell accumulation in glioblastoma with a potential role for stem cell factor and chemokine CXCL12. PLoS ONE 6:e25222 Reszec J, Hermanowicz A, Rutkowski R et al (2013) Evaluation of mast cells and hypoxia inducible factor-1 expression in meningiomas of various grades in correlation with peritumoral brain edema. J Neurooncol 115:119–125 Rojas IG, Spencer ML, Martinez A et al (2005) Characterization of mast cell subpopulations in lip cancer. J Oral Pathol Med 34:268–273 Samoszuk M, Corwin M (2003) Mast cell inhibitor cromolyn increases blood clotting and hypoxia in murine breast cancer. Int J Cancer 107:159–163 Sharma VK, Agrawal AK, Pratarp VK et al (1992) Mast cell reactivity in lymphoma: a preliminary communication. Indian J Cancer 29:61–65 Stack MS, Johnson DA (1994) Human mast cell tryptase activates single-chain urinary-type plasminogen activator (pro-urokinase). J Biol Chem 269:9416–9419 Theoharides T, Conti P (2004) Mast cells: the jekyll and hyde of tumor growth. Trends Immunol 25:235–241 Theoharides TC, Kempuraj D, Tagen M et al (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 217:65–78 Theoharides TC, Rozniecki JJ, Sahagian G et al (2008) Impact of stress and mast cells on brain metastases. J Neuroimmunol 205:1–7 Thoresen S, Tangen M, Hartveit F (1982) Mast cells in the axillary nodes of breast cancer patients. Diagn Histopathol 5:65–67 Torunilhac O, Santos DD, Xu L et al (2006) Mast cells in waldenstrom’s macroglobulinemia support lymphoplasmacytic cell growth through CD154/CD40 signaling. Ann Oncol 17:1275–1282 Travis WD, Li CY, Yam LT et al (1988) Significance of systemic mast cell disease with associated hematologic disorders. Cancer 62:965–972 Welsh TJ, Green RH, Richardson D et al (2005) Macrophage and mast cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 23:8959–8967

Chapter 11

Mast Cells in Tumor Angiogenesis and Lymphangiogenesis

11.1 Mediators Released by Human Mast Cells Involved in the Angiogenic Response The ability of mast cells to store angiogenic growth factors and their cell-specific release of preformed factors into the surrounding tissue by piecemeal degranulation (Dvorak and Kissel 1991) indicate that their granules are a depot for endothelial survival factors. Piecemeal degranulation is also of clinical significance in diseases characterized by fibroproliferation and neovascularization (Dvorak 1992). Mast cells syntesize and store large amounts of MMPs (Fang et al. 1999; Di Girolamo et al. 2000; Vincent et al. 2000). Given the ability of MMP-2 and MMP-9 to degrade type IV, V, VII and X collagens, as well as fibronectin, namely the major components of the interstitial stroma and subendothelial basement membrane, the findings suggest that mast cells may contribute to the progression from in situ to invasive and metastatic solid tumors, characterized by an enhanced angiogenesis and secretion of proteolytic enzymes (Raza and Cornelius 2000). Mast cells are also a rich source of proteases, specifically tryptase (Schwartz et al. 1981; Hopsu and Glenner 1963) and chymase (Wintroub et al. 1986; Sayama et al. 1987). Tryptase is the predominant protease present in mast cell granules in the lung, skin and gastrointestinal tract, while chymase is present in 85% of the mast cells of the skin and intestinal submuosa, but not in the intestinal mucosa or lung. Both enzymes are involved in angiogenesis following their release from the granules of activated mast cells. Their proteolytic activities directly degrade extracellular matrix components or release matrix-associated growth factors (Taipale et al. 1995), and they also act more indirectly by activating latent matrix-degrading metalloproteases (Gruber et al. 1989). Blair et al (1997) have investigated in vitro the angiogenic potential of tryptase released by mast cells and demonstrated its important role in neovascularization. Tryptase added to microvascular endothelial cells cultured on Matrigel caused a pronounced increase of capillary growth, and this was suppressed by specific tryptase inhibitors. Moreover, tryptase directly induced endothelial cell proliferation in a dose-dependent fashion. © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_11

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Muramatsu et al. (2000a, b) used the hamster sponge-implant model to show that angiogenesis is induced by angiotensin II and inhibited by chymase inhibitors, suggesting that mast cell-derived chymase is an important mediator of mast celldependent angiogenesis. Other mast cell-specific mediators with angiogenic properties include histamine and heparin (Norrby 1985; Ribatti et al. 1987). Heparin stimulates endothelial cell proliferation and migration in vitro (Thorton et al. 1983; Alessandri et al. 1984). In vivo, however, it has been found to stimulate (Ribatti et al. 1987; Norrby and Sorbo 1992; Norrby 1993), inhibit (Jakobson and Hahnenberger 1991; Wilks et al. 1991; Norrby 1993) or have no effect (Castellot et al. 1982; Taylor and Folkman 1982), though these differences seem to be related to its molecular size and degree of sulfation. The 22- and 2.4-kDa heparin fractions display stimulatory and inhibitory properties respectively (Norrby 1993) N-sulphate, but not O-sulphate, groups are necessary for the release of the extracellular matrix (heparan sulphate)-bound FGF2, in that their total replacement by acetyl or hexanoyl groups, despite the normal Osulphate content, abolishes the FGF-2-releasing activity (Ishai-Michaeli et al. 1992). Heparin acts as a soluble form of the low-affinity FGF-2 receptor (Folkman and Shing 1992), which displaces FGF-2 in the biologically active form, allowing its rapid interaction with endothelial cells (Yayou et al. 1991). Protamine sulphate, a heparin inhibitor, blocks angiogenesis (Taylor and Folkman 1982). Heparanase is closely involved in angiogenesis, both directly by promoting invasion of endothelial cells (vascular sprouting), and indirectly by releasing heparan sulfate-bound FGF-2 and generating heparan sulfate degradation fragments that promote FGF-2 activity (Vlodavski et al. 2000). Protamine, a heparin antagonist, prevented heparin from enhancing angiogenesis and was able to inhibit tumor angiogenesis (Taylor and Folkman 1982). The inhibitory effect of protamine could be overcome by excess heparin (Majewski et al. 1984). Heparanase is released by mast cells (Bashkin et al. 1990) and can release active heparin sulphate-bound FGF-2 from the extracellular matrix of endothelial cells (Vlodasky et al. 1992). Histamine has an angiogenic effect through both H1 and H2 receptors (Sorbo et al. 1994). Histamine might also contribute to the hyperpermeable nature of newly formed microvessels during pathological angiogenesis. The increased vascular permeability induced by histamine may increase leakage of plasma proteins and hence deposition of fibrin. Degradation products of fibrin are angiogenic in the chick embryo CAM (Thompson et al. 1995). Norrby et al. (1986) demonstrated that active mast cell secretion induced by repeated intraperitoneal injection of compound 48/80, a highly selective mast cell secretagogue, resulted in marked mesenteric neovascularization in rats and mice, as determined by the vascularized area and the vascular density. Further indirect support to a functional link between mast cells and neovascularization was obtained by Roche (1985) in cell culture experiments showing that isolated rat and mouse mast cell granules are mitogenic to human venous endothelial cells. Moreover, rat mast cell granules added to cultured human microvascular endothelial cells exerted a marked proliferative effect (Marks et al. 1986). Adrenomedullin, a 52-amino acid peptide originally isolated from human pheochromocytomas, is another molecule which plays a critical role in the cross-

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talk between tumor cells and mast cells. Adrenomedullin is an important regulator of mast cell function related to tumour promotion (Zudaire et al. 2006). Indeed, adrenomedullin induces histamine or β-hexosaminidase release from rat and human mast cells through a receptor-independent pathway. It is chemotactic for human mast cells and stimulates mRNA expression of VEGF, MCP-1 and FGF-2 in these cells. Immunohistochemical analysis has identified adrenomedullin-producing mast cells in tumor infiltrate of human breast and lung cancer patients. In mixed culture assay, the adrenomedullin-producing human mast cell line HMC-1 augments both anchorage-dependent and -independent growth of human lung cancer A549 cells, an effect suppressed by MC-targeted siRNA adrenomedullin knockdown. Finally, HMC-1 cells induce in vivo angiogenesis as assessed by direct in vivo angiogenesis assay analysis; neutralizing anti-adrenomedullin monoclonal antibody blocks this ability. Thus, adrenomedullin appears to be implicated as a cross-talk molecule in tumor and mast cell communication during cancer promotion.

11.2 The CAM Assay in the Study of Mast Cell Induced Angiogenesis The CAM is an extraembryonic membrane which serves as a gas exchange surface (Romanoff 1960), and its function is supported by an extensive capillary network. It is utilized as a target for the study of angiogenic and anti-angiogenic compounds. Histamine and heparin stimulate proliferation of endothelial cells and induce the formation of new blood vessels in the CAM assay (Thompson and Brown 1987; Ribatti et al. 1987). Activation of connective tissue mast cells by compound 48/80 promoted angiogenesis in the CAM (Clinton et al. 1988). In addition, Kessler et al. (1976) reported that a 40-fold increase in the number of mast cells preceded angiogenesis induced by tumor implants in the CAM. We have compared the angiogenic potential of cell suspensions of mast cells isolated from rats, degranulated mast cells and their secretory granules adsorbed on gelatin sponges and implanted on top of the developing CAM (Fig. 11.1) (Ribatti et al. 2001a, b). Results showed that isolated mast cells and their secretory granules, but not degranulated mast cells, induced an angiogenic response. Addition of anti-FGF-2 or anti-VEGF antibodies reduced these responses by 50 and 30% respectively.

11.3 Mast Cells in Experimental Tumor Angiogenesis Experimentally induced tumors display mast cell accumulation close to the tumor cells before the onset of angiogenesis (Kessel et al. 1976). Likewise, an increase in mast cell number has been observed in tumor invasion around rat adenocarcinoma and in hamster epidermal carcinoma (Dabboue et al. 1986). Angiogenesis is

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Fig. 11.1 A mast cell suspension has been delivered on the top of the chick embryo chorioallantoic membrane at day 8 of incubation using a gelatin sponge implant. Macroscopic observation at day 12 shows the gelatin sponge surrounded by numerous allantoic vessels that develop radially towards the implant in a ‘spoked-wheel’ pattern (a). The histological analysis shows among the sponge trabeculae metachromatic mast cells and their secretory granules (b). Reproduced from Ribatti et al. (2001a)

restored after local reconstitution of mast cells (Starkey et al. 1988). Kessler et al. (1976) demonstrated that tumor angiogenesis factor (TAF) elicited a vasoproliferative response when implanted upon the CAM of the chick embryo. This response was first observed stereomicroscopically 2–3 days after implantation and a 40-fold increase in mast cell density was observed in the vicinity of the implants by 24 h. Poole and Zetter (1983) demonstrated that rat peritoneal mast cells migrate in response to conditioned medium from several tumor cell lines. The active chemoattractant(s) in this conditioned medium appeared to be peptide(s) with a molecular weight of 300–1000. They proposed that the chemoattraction of mast cell by tumorderived peptides may be an important early event in tumor neovascularization. Tumors induced in mast cell-deficient mice display both reduced angiogenesis and ability to metastasize (Starkey et al. 1988; Dethlefsen et al. 1994). Starkey et al. (1988) investigated the role of host mast cell in tumor-associated angiogenesis by comparing the angiogenic response of genetically mast cell-deficient W/Wv mice and mast cell-sufficient +/+ litter mates to subcutaneously growing B16-BL6 tumors. The response was slower and initially less intense in W/Wv . Fewer W/Wv than + /+ mice developed spontaneous lung metastases. Bone marrow repair of the mast cell deficiency restored the incidence of hematogeneous metastases to approach that of +/+ mice. These results demonstrate a role for mast cell in vivo during tumor angiogenesis and also suggest a role for host mast cell in hematogeneous metastases. Coussens and Web (1996) reported that expression of HPV 16 early-region genes in basal keratinocytes of transgenic mice elicits a multistage pathway to squamous carcinoma. Infiltration by mast cell and activation of MMP-9 in mast cells and leukocytes coincided with the angiogenic switch in premalignant lesions. Mast cells release

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specific proteases, MCP-4 (chymase) and MCP-6 (tryptase). MCP-4 activates progelatinase A, itself a component of mast cell granules, releases sequestered angiogenic factors, such as VEGF and FGF-2 from neoplastic skin, and thus induces angiogenesis. MCP-6 induces normally quiescent fibroblasts to participate in the formation of neoplastic stroma.

11.4 Mast Cells and Angiogenesis in Solid Tumors Ehrlich (1879) found many mast cells in tumors, especially carcinomas. It was left to his pupil, Westphal (1891), to recognize that they tend to congregate at the periphery of carcinomatous nodules, rather than in the core of a tumor. Mast cells are recruited and activated via several factors secreted by tumor cells: the c-kit receptor, or stem cell factor (Poole and Zetter 1983; Norrby and Wooley 1993), as well as FGF-2, VEGF and PDGF, which are operative at picomolar concentrations (Gruber et al. 1995). Mast cell accumulation has been associated with enhanced growth and invasion of human mammary carcinoma (Hartveit 1981; Hartveit et al. 1984), cervical carcinoma (Dunn and Montogomery 1957), gastric cancer (Yano et al. 1999), colorectal cancer (Fisher et al. 1989; Nielsen et al. 1999; Tan et al. 2005), hemangioma (Glowacki and Millitan 1982; Qu et al. 1995), Kaposi’s sarcoma (Hagiwara et al. 1999), lung cancer (Takanami et al. 2000; Tomita et al. 2000), laryngeal squamous cell carcinoma (Sawatsubashi et al. 2000), papillary thyroid carcinoma (Melillo et al. 2010) and a variety of skin tumors (Cawley and Hochi-Ligeti 1961). Glowacki and Millitan (1982) found that the density of mast cells in rapidly forming hemangiomas was at least five times higher than in normal skin and that the mast cell number fell to normal when they regressed. In prostate cancer, the number of tryptase-positive mast cells correlate with a high Gleason score and an advanced clinical stage of the tumor (Nonomura et al. 2007). Moreover, high intratumoral mast cell density may be associated with a good or poor prognosis in prostate cancer (Fleischmann et al. 2009; Johansson et al. 2010). An association of VEGF and mast cell with angiogenesis has been demonstrated in laryngeal carcinoma (Sawatsubashi et al. 2000), papillary thyroid carcinoma (Melillo et al. 2010), in small lung carcinoma, where most intratumoral mast cells express VEGF (Imada et al. 2000; Takanami et al. 2000; Tomita et al. 2000), and in melanoma, where mast cells express both VEGF (Toth et al. 2000) and FGF-2 (Ribatti et al. 2003a). Increased number of mast cells correlates with either a good (Tomita et al. 1999; Welsh et al. 2005; Carlini et al. 2010) or poor prognosis (Takanami et al. 2000) in non small cell lung cancer. Also in breast carcinoma, an increased number of mast cells is correlated with a good (Aaltomaa et al. 1993; Dabiri et al. 2004; Rajput et al. 2008; Della Rovere et al. 2007) or a poor (Xiang et al. 2010; Ribatti et al. 2007a, b) prognosis. A prognostic significance has been attributed to mast cell and microvascular density in squamous cell cancer of the oesophagus (Elpek et al. 2001) and in melanoma (Ribatti et al. 2003b).

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The functional significance of tumor-infiltrating mast cells is not entirely clear. They are thought to act as a host response to neoplasia (Nakanishi et al. 1994) and display tumouricidal activity in some in vitro assays (Henderson et al. 1981). However, their accumulation has also been observed in experimentally induced tumors before the onset of tumor-associated angiogenesis (Kessel et al. 1976). On the other hand, tumors in mast cell-deficient mice have reduced vascularity and produce fewer metastases (Starkey et al. 1988; Dethlefsen et al. 1994). These findings point to a direct involvement of mast cells in tumor angiogenesis by releasing several angiogenic factors through the release of specific angiogenic cytokines or modulators of angiogenesis from their secretory granules.

11.5 Mast Cells and Angiogenesis in Hematological Malignancies We have demonstrated that angiogenesis is correlated with tumor growth (S-phase fraction) in monoclonal gammopathies of undetermined significance (MGUS) and multiple myeloma (MM) grouped according to a pathway of progression (Vacca et al. 1994, 1999), and with progression stages both in B-cell NHL (B-NHL) (Ribatti et al. 1996). Patients with active MM have elevated levels of angiogenic cytokines, such as FGF-2 and VEGF, with a role in both tumor cell growth and survival, and in bone marrow angiogenesis (Vacca et al. 1999). Furthermore, neovascularization, plasma cell angiogenic potential and MMP-2 secretion parallel disease progression (Vacca et al. 1999). Angiogenesis in benign lymphadenopathies and B-cell non Hodgkin’s lymphomas (B-NHL), measured as microvessel counts, is correlated with the total metachromatic and mast cell tryptase-positive counts, and that both counts increase in step with the increase in Working Formulation malignancy grades (Ribatti et al. 1998, 2000). Moreover, we have shown that bone marrow angiogenesis, evaluated as microvessel area, and mast cell counts are highly correlated in patients with non-active and active MM and in those with MGUS, and that both parameters increase simultaneously in active MM (Fig. 11.2) (Ribatti et al. 1999). In B-NHL and MM, mast cells are located near or around blood or lymphatic capillaries. Their ultrastructural picture includes a morphological semilunar feature (Fig. 11.3), or piecemeal partial degranulation of their secretory granules, unlike the IgE-mediated massive degranulation that occurs during immediate hypersensitivity reactions. This morphology is typical of the slow degranulation that takes place in delayed hypersensitivity reactions and chronic inflammation (Kops et al. 1984; Ribatti et al. 1988). In B-NHL and MM, the semilunar appearance may reflect slow but progressive release of angiogenic factors, favouring chronic and progressive stimulation of mast cell degranulation. Fukushima et al. (2001) found a significant correlation in NHL between vessel count and the number of both mast cell and VEGF-expressing cells. Double fluorescence staining of VEGF mRNA and mast cell tryptase revealed that mast cells expressed VEGF mRNA.

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Fig. 11.2 Mast cell counts in comparison with the microvessel area in the bone marrow of patients with active and non-active multiple myeloma (MM) and with monoclonal gammopathy of undetermined significance (MGUS). Significance of the regression analysis was calculated by the Pearson’s (r) test. Modified from Ribatti et al. (1999)

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Fig. 11.3 Ultrastructural findings of mast cell granules from high-grade human B-non Hodgkin’s lymphoma. Note in a, a heterogeneous mixture consisting of coarse particles and scrolls, thick threads and finely granular material or a mixture of this and scrolls. Note in b, a semilunar (piecemeal) granular aspect and in c, a full complement of dense particles recognizable in this type of granule. Reproduced from Crivellato et al. (2002)

Bone marrow samples of patients with myelodysplastic syndromes display a high correlation between microvessel counts and both total and tryptase-positive mast cells, and that both parameters increase simultaneously with tumor progression (Ribatti et al. 2002). There is also a correlation between the extent of angiogenesis and the number of tryptase-positive mast cells in patients with early B-cell chronic lymphocytic leukaemia and tryptase-postive mast cells predict their clinical outcome (Molica et al. 2003; Ribatti et al. 2003a, b).

11.6 Mast Cells and Tumor Lymphangiogenesis Mast cells also promote lymphangiogenesis. Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis and tumour growth. In transgenic J4 mice, which overexpress endostatin in their keratinocytes, carcinogen-induced skin squamous cell carcinomas were less aggressive and more often well differentiated than those in the control mice, indicating that endostatin regulates the terminal differentiation of keratinocytes (Brideau et al. 2007). Tumor angiogenesis was inhibited by endostatin at an early stage in skin tumour development. Inhibition of angiogenesis was accompanied by significant reduction of lymphatic vessels and lymph node metastasis. Accumulation of tumor-infiltrating VEGF-C-positive mast cells was markedly decreased in the tumors of the J4 mice. In addition, endostatin inhibited the adhesion and migration of murine mast cells on fibronectin in vitro. These

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data suggest that endostatin can inhibit tumor lymphangiogenesis by decreasing the VEGF-C levels in the tumors via inhibition of mast cell migration and adhesion. The role of mast cells in draining lymph nodes, in tertiary lymphoid tissues and at metastatic sites remains to be explored.

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Molica S, Vacca A, Crivellato E et al (2003) Tryptase-positive mast cells predict clinical outcome of patients with early B-cell chronic lymphocytic leukemia. Eur J Haematol 71:137–139 Muramatsu M, Katada J, Hattori M et al (2000a) Chymase as a proangiogenic factor; a possible involvement of chymase-angiotensin-dependent pathway in the hamster sponge angiogenesis model. J Biol Chem 275:5545–5552 Muramatsu M, Katada J, Hattori M et al (2000b) Chymase mediates mast cell-induced angiogenesis in the hamster sponge granuloma. Eur J Pharmacol 402:181–191 Nakanishi H, Oguri K, Takenaga K et al (1994) Differential fibrotic stromal responses of host tissue to low- and high-metastatic cloned lewis lung carcinoma cells. Lab Invest 70:324–332 Nielsen HJ, Hansen U, Christensen IJ et al (1999) Independent prognostic value of eosinophil and mast cell infiltration in colorectale cancer tissue. J Pathol 189:487–495 Nonomura N, Takayama H, Nishimura K et al (2007) Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer. Br J Cancer 97:952–956 Norrby K (1985) Evidence of mast cell histamine being mitogen in intact tissue. Agents Actions 16:287–290 Norrby K (1993) Heparin and angiogenesis: a low molecular weight fraction inhibits and a highmolecular weight fraction stimulates angiogenesis systematically. Haemostasis 23:144–149 Norrby K, Sorbo J (1992) Heparin enhances angiogenesis by a systemic mode of action. Int J Exp Pathol 73:1451–1455 Norrby K, Woolley D (1993) Role of mast cells in mitogenesis and angiogenesis in normal tissue and tumour tissue. Adv Biosci 89:71–116 Norrby K, Jakobsson A, Sorbo J (1986) Mast-cell-mediated angiogenesis: a novel experimental model using the rat mesentery. Virchows Arch B Cell Pathol Incl Mol Pathol 52:195–206 Poole TJ, Zetter BR (1983) Mast cell chemotaxis to tumor derived factors. Cancer Res 43:5857–5862 Qu Z, Liebler JM, Powers MR et al (1995) Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am J Pathol 147:564–573 Raiput AB, Turbin DA, Cheang MC et al (2008) Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4.444 cases. Breast Cancer Res Treat 107:249–257 Raza SL, Cornelius LA (2000) Matrix metalloproteinases: pro- and anti-angiogenic activities. J Investig Dermatol Symp Proc 5:47–54 Ribatti D, Roncali L, Nico B et al (1987) Effects of exogenous heparin on the vasculogenesis of the chorioallantoic membrane. Acta Anat (Basel) 130:257–263 Ribatti D, Contino R, Tursi A (1988) Do mast cells intervene in the vasoproliferative processes of the rheumatoid synovitis? J Submicrosc Cytol Pathol 20:635–637 Ribatti D, Nico B, Vacca A et al (1998) Do mast cells help to induce angiogenesis in B-cell nonhodgkin’s lymphomas? Br J Cancer 77:1900–1906 Ribatti D, Vacca A, Nico B et al. (1996) Angiogenesis spectrum in the stroma of B cell non Hodgkin’s lymphoma. An immunohistochemical and ultrastructural study. Eur J Haematol 56:45–53 Ribatti D, Vacca A, Nico B et al (1999) Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer 79:451–455 Ribatti D, Vacca A, Marzullo A et al (2000) Angiogenesis and mast cell density with tryptase activity increase simultaneously with pathological progression in B-cell non-hodgkin’s lymphomas. Int J Cancer 85:171–175 Ribatti D, Crivellato E, Candussio L et al (2001a) Mast cells and their secretory granules are angiogenic in the chick embryo chorioallantoic membrane. Clin Exp Allergy 31:602–608 Ribatti D, Vacca A, Nico B et al (2001b) The role of mast cells in tumour angiogenesis. Brit J Haematol 115:514–521 Ribatti D, Polimeno G, Vacca A et al (2002) Correlation of bone marrow angiogenesis and mast cells with tryptase activity in myelodysplastic syndromes. Leukemia 16:1680–1684 Ribatti D, Vacca A, Ria R et al (2003a) Neovascularization, expression of fibroblast growth factor2, and mast cell with tryptase activity increase simultaneously with pathological progression in human malignant melanoma. Eur J Cancer 39:666–765

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Ribatti D, Molica S, Vacca A et al (2003b) Tryptase-positive mast cells correlate positively with bone marrow angiogenesis in B-cell chronic lymphocytic leukemia. Leukemia 17:1428–1430 Ribatti D, Nico B, Crivellato E et al (2007a) Macrophages and tumor angiogenesis. Leukemia 21:2085–2089 Ribatti D, Finato N, Crivellato E et al (2007b) Angiogenesis and mast cells in human breast cancer sentinel lymph node with and without micrometastasis. Histopathology 51:837–842 Roche WR (1985) Mast cells and tumor angiogenesis: the tumor-mediated release of an endothelial growth factor from mast cells. Int J Cancer 36:721–728 Romanoff AL (1960) The avian embryo: structural and functional development. MacMillan, New York Sawatsubashi M, Yamada T, Fukushima N et al (2000) Association of vascular endothelial growth factor and mast cells with angiogenesis in laryngeal squamous cell carcinoma. Virchows Arch 436:243–248 Sayama S, Iozzo RV, Lazarus GS et al (1987) Human skin chymotrypsin-like proteinase chymase. Subcellular localization to mast cell granules and interaction with heparin and other glycosaminoglycans. J Biol Chem 262:6808–6815 Schwartz LB, Lewis RA, Austen KF (1981) Tryptase from human pulmonary mast cells. Purification and Characterization. J Biol Chem 256:11939–11943 Sorbo J, Jakobson A, Norrby K (1994) Mast cell histamine is angiogenic through receptors for histamine 1 and histamine 2. Int J Exp Pathol 75:43–50 Starkey JR, Crowle PK, Taubenberger S (1988) Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis. Int J Cancer 42:48–52 Taipale J, Lohi J, Saarinen J et al (1995) Human mast cell chymase and leukocyte elastase release latent transforming growth factor beta-1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem 270:4689–4696 Takanami I, Takeuchi K, Naruke M (2000) Mast cell density is associated with angiogenesis and poor prognosis in pulmonary adenocarcinoma. Cancer 88:2686–2692 Tan SY, Fan Y, Luo HS et al (2005) Prognostic significance of cell infiltrations of immunosurveillance in colorectal cancer. World J Gastroenterol 11:1210–1214 Taylor S, Folkman J (1982) Protamine is an inhibitor of angiogenesis. Nature 297:307–312 Thompson WD, Brown FI (1987) Quantitation of histamine-induced angiogenesis in the chick chorioallantoic membrane: mode of action of histamine is indirect. Int J Microcirc Clin Exp 6:343–357 Thompson WD, Campbell R, Evans T (1995) Fibrin degradation and angiogenesis: quantitative analysis of the angiogenic response in the chick chorioallantoic membrane. J Pathol 145:27–37 Thorton SC, Mueller SM, Levine EM (1983) Human endothelial cells: use of heparin in cloning and long term cultivation. Science 222:623–625 Tomita M, Matsuzaki Y, Onitsuka T (1999) Correlation between mast cells and survival rates in patients with pulmonary adenocarcinoma. Lung Cancer 26:103–109 Tomita M, Matsuzaki Y, Onitsuka T (2000) Effect of mast cells on tumor angiogenesis in lung cancer. Ann Thorac Surg 69:1686–1690 Toth T, Toth-Jakatics R, Jimi S et al (2000) Cutaneous malignant melanoma: correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. Hum Pathol 31:955–960 Vacca A, Ribatti D, Roncali L et al (1994) Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 87:503–508 Vacca A, Ribatti D, Presta M et al (1999) Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93:3064–3073 Vincent AJ, Zhang J, Ostor A et al (2000) Matrix metalloproteinase-1 and-3 and mast cells are present in the endometrium of women using progestin-only contraceptives. Hum Reprod 15:123–130

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Chapter 12

Mast Cells as Therapeutic Target in Cancer

12.1 Background Reducing mast cells number is a therapeutic approach in mastocytosis and other diseases in which mast cells number is increased. The number of mast cells may be reduced by the targeted induction of apoptosis or by blocking their recruitment, migration and differentiation. Many pharmacological agents have been developed that modulates mast cell functions. They block mediator receptors on target cells, including H1 receptor antagonists, CysLT1 receptor antagonists PGD2 receptors antagonists; inhibit mast cell mediator synthesis, including omalizumab, disodium cromoglycate and imatinib; block mast cell activation or mediator release, including steroids and non steroidal anti-inflammatory drugs (NSAIDs). Actually, there are no pharmacologic agents that can solely and selectively suppress mast cell activation (Reber et al. 2012). Mastocytosis patients with skin manifestations are treated with topical glucocorticoids for several weeks which are able to reduce cutaneous mast cells number (Pipkorn et al. 1989). Mast cell biological activity may be in the same time synergic and compensatory in the tumor context and identification and targeting of mast cells represents an attractive therapeutic approach in cancer. Therapeutic strategies include inhibition of recruitment of mast cells to the tumor microenvironment and blockade of pro-tumoral and pro-angiogenic effects.

12.2 Inhibition of the SCF/Kit Axis The tyrosine kinase receptor Kit (CD117) is upregulated in tumor cells and mutations in c-kit are associated to the development of gastrointestinal stromal tumor (GIST), in various forms of mastocytosis and mast cell leukemia (Pittoni et al. 2011a). Mast cells express high levels of c-kit and SCF, the ligand for kit, is produced by mast cells and is involved in their development, survival, migration, and function (Ribatti © Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2_12

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and Crivellato 2014). SCF enhances tumor growth through increased production of VEGF, IL-6, IL-10, and TNFα (Huang et al. 2008). Inhibition of the SCF/Kit axis in vivo inhibits the migration of mouse bone marrow—derived cultured mast cells to tumors in a transplanted tumor model in mice (Huang et al. 2008).

12.3 Tyrosine-Kinase Inhibitors Neoplastic mast cells are resistant against conventional cytostatic drugs (Arock and Valent 2010). Systemic mastocytosis is a myeloid disorder characterized by abnormal growth and accumulation of neoplastic mast cells in internal organs (Metcalfe 2008). Imatinib which blocks both CD117 and PDGFRα protein tyrosine kinase activities, has been developed for treatment of chronic myelogenous leukemia. Long term treatment of patients with chronic myeloid leukemia (CML) with imatinib resulted in a reduction of bone marrow mast cell number to 5% of pre-treatment values accompanied by a significant decrease in serum tryptase levels (Cerny-Reiter et al. 2015).The first tyrosine kinase inhibitor introduced into the clinic STI571 (Imatinib mesylate, Gleevec) has been used for some varieties of mastocytosis, although some kit activating mutations (kit D816V) involved in mastocytosis are resistant to it inhibitory activity (Akin and Metcalfe 2004). In a murine model of breast carcinoma, depletion of mast cells with imatinib mesylate enhanced tumor growth (Samoszuk and Corwin 2003a, b). In a majority of all patients with systemic mastocytosis the transforming kit mutation D816V is detectable (Gotlib 2006) and most kit inhibitors cannot block the mutated Kit (Ustun et al. 2011). KitD816V has been developed as a therapeutic target in mast cell tumors and several of the new tyrosine kinase inhibitors, including midostaurin (PKC412), nilotinib (AMN107), and dasatinib, counteract malignant cell growth in patients with aggressive systemic mastocytosis or mast cell leukemia (Gleixner et al. 2007; Gotlib et al. 2005; Schittenhelm et al. 2006; Shah et al. 2006; von Bubnoff et al. 2005). Sunitinib inhibits c-kit mutations in systemic mastocytosis (Prenen et al. 2006); however, neither sasatinib nor midistaurin induce long-lasting complete remission. The multi-kinase inhibitor DCC-2618 which inhibits the growth of neoplastic mast cells in vitro, has entered clinical investigation (Schneeweiss et al. 2016). Targeting of Siglec-8, which is exclusively expressed by mast cells, may allow fro reducing mast cells number in mastocytosis (Kiwamoto et al. 2012). Masatinib is a tyrosine kinase inhibitor that targets c-kit receptors and is clinically developed and approved for treatment of recurrent or unresectable grade III dog mast cell tumors and is the first approved anticancer drug in veterinary medicine (Dubreuil et al. 2009). Masatinib has been translated to human clinical trials for evaluating in GIST, mastocytosis and pancreatic cancer (Le Cesne et al. 2010; Mitry et al. 2010).Imatinib, nilotinib, and dasatinib inhibit the protein tyrosine kinase BCR/ABL and are used in the treatment of chronic myeloid leukemia (Ustun et al. 2011).

12.4 Other Molecules

105

12.4 Other Molecules Several drugs stabiling mast cells (Table 12.1) are used in the clinic to treat mast celldriven disorders (Zhang et al. 2016). Obatoclax (GX015-070), a novel BH3 mimetic, small molecule-type-targeted drug that binds and blocks the antiapoptotic activity of several members of the Bcl-2 family, induces growth arrest in primary human and canine neoplastic mast cells, as well as in different mast cell lines (Peter et al. 2014). Obatoclax exerts synergistic antineoplastic effects on MCs when combined with dasatinib (Peter et al. 2014). Administration in mouse models of anti-TNF-α antibodies (Gounaris et al. 2007), or the mast cell stabilizer disodium cromoglycate (cromolyn) (Soucek et al. 2007) is effective on tumor growth. Cromolyn exerts its effects also on neutrophils and eosinophils. Intraarticular treatment with cromolyn (Moqbel et al. 1986) prevents angiogenesis, pannus formation and joint destruction in experimental arthritis in mice (Kneilling et al. 2007). When TRAMP mice were treated with cromolyn, such mice developed a rare neuroendocrine cancer characterized by ckit expression, suggesting that mast cells exert a protective role in the development of these tumors (Pittoni et al. 2011a, b). Santos et al. (2006) demonstrated that CD42 is expressed on bone marrow mast cells from patients with Waldenstrom’s macroglobulinemia and that alentuzumab could be used to induce antibody-dependent cytoxicity against mast cells. Molica et al. (2007) demonstrated that the reduction of extent of bone marrow angiogenesis after sequential therapy with low doses of subcutaneous alentuzumab after a clinical response to fludarabine induction therapy was associated to a reduction in the number of bone marrow mast cells.Silymarin, a naturally derived polyphenolic anti-oxidant, may exert beneficial effects on liver carcinogenesis by reducing the recruitment of mast cells and the expression of MMP-2 and MMP-9 (Ramakrishnan et al. 2009). Toceranub phosphate (SU11654) is an indolinone kinase inhibitor with both anti-tumor and anti-angiogenic activity through inhibition of c-kit receptor, VEGFR-2, and PDGF receptor beta (PDGFRβ), used as inhibitor of kit phosphorylation in canine mast cell tumors (London et al. 2003; Pryer et al. 2003). H1 receptor antagonists significantly improved overall survival rates and suppressed tumor growth as well as the infiltration of mast cells and VEGF levels through the inhibition of hypoxia inducible factor-1 alpha (HIF-1α) expression in B16F10 melanoma-bearing mice (Jeong et al. 2013). Treatment of mice with cimetidine, an H2 receptor antagonist, slow the growth of melanoma and breast cancer (Bowrey et al. 2000; Nordlund and Askenase 1983). Chondroitin sulphate may inhibit tumor cells diffusion and tryptase causes both tumor cell disruption and inflammation through activation of protease-activated receptors (PAR-1 and -2) (Ribatti and Crivellato 2012). Gabexate mesylate is a synthetic inhibitor of trypsine-like serine proteases (Menegatti et al. 1986). The anti-invasive, anti-metastatic, and anti-angiogenic activities of gabexate mesylase could be also explained through the inhibition of human mast cell tryptase (Erba et al. 2001). Brandi et al. (2012) demonstrated that gabexate

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12 Mast Cells as Therapeutic Target in Cancer

Table 12.1 Drugs stabilizing mast cells Cromolyn sodium Nedocromil Lodoxamide Antagonists for the histamine receptor H1 (Azelastine, Ketotifen, Olopatidine, Bilastine, Desloratidine, Rupatidine, Epinastine)

mesylate inhibited growth, invasiveness and tumor-induced angiogenesis harbouring KRAS, BRAF and PIK3CA mutations. Yoon et al. (2004) produced similar evidence and shiwed that gabexate mesylate activity was mediated by down-regulation of MMPs and inhibition of uPA-plasmin system. Nofamostat mesylate is able to inhibit a variety of trypsin-like serine proteases (Aoyama et al. 1984). Intraperitoneal administration of pancreatic cancer cells, pretreated with nofamostat mesylate in nude mice, is followed by reduced peritoneal metastasis and neovascularization, an increased survival compared with controls through nuclear factor kappa-B inhibition (Fujiwara et al. 2011). Steroid treatment can reduce mast cells number in vivo (Pipkorn et al. 1989), through induction of mast cell apoptosis (Johnson et al. 1988) and effects on progenitor recruitment and differentiatn (Irani et al. 1995; Smith et al. 2002).

12.5 Perspectives Some of the new targeted anti-cancer therapies may exert effects on mast cells (Table 12.2). Chemoprevention with an anti-inflammatory approach has the potential to inhibit neovascularization before the onset of the angiogenic switch, resulting in a significant delay in tumor growth. Moreover, the development of novel therapies to alter mast cell function in the tumor microenvironment could inhibit tissue remodeling and tumor growth and activate the immune system. In the light of the present knowledge, mast cells might be regarded in a future perspective as a new target for the adjuvant treatment of tumors through the selective inhibition of angiogenesis, tissue remodelling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression. Moreover, some of the new targeted anti-cancer therapies have pronounced effects on mast cells: it may be that some of their anti-tumor effect is closely related to their effect on mast cells.

References Table 12.2 Anti-tumor drugs that target regulatory mast cell molecules

107

Drug

Main target in mast cell

Imatinib mesylate (Gleevec, ST1571)

c-kit

Sorafenib

c-kit

Sunitinib

c-kit

Pazopanib (GW786034)

c-kit

Axitinib

c-kit

Dasatinib

c-kit

Enzastaurin

PKC-beta

Alemtzumab (Campath)

CD52

CpG activator (Promune)

TLR9

MDX 060

CD30 (ligand for CD301)a

Tanespimycin (17AAG)

Heat shock protein 90 beta

a Involved

in the regulation of regulate chemokine secretion by

mast cells

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Index

A Adaptive immune response, 36, 40 Alcian blue, 15, 17, 18 Allergy, 42, 76, 77 ANCA-associated vasculitis, 61 Angiogenesis, 27, 36, 42, 44, 51, 52, 55, 59, 63, 64, 70–72, 75, 77, 78, 81, 82, 89–94, 96, 105, 106 Angiogenic factors, 27, 37, 52, 54, 55, 64, 78, 81, 82, 93, 94 Arteriogenesis, 51–55 Atherosclerosis, 42, 44, 45, 51, 54 B Basophils, 7, 8, 18, 75–78 B cells, 41, 42, 84 Behcet’s disease, 61–63 Blood-brain barrier, 67–70, 72, 85 Bone marrow, 5–11, 16, 19, 53, 54, 75, 76, 85, 92, 94–96, 104, 105 Brain tumor, 68, 70–72, 85 C Cell adhesion molecule, 9, 52, 53 Chemokine receptor, 10, 40, 53, 78, 85 Chemokines, 10, 30, 31, 36, 37, 39, 40, 42, 53, 55, 59, 60, 75–78, 85, 107 Chorioallantoic membrane, 92 Chymase, 8, 19, 20, 25–28, 31, 35, 37, 38, 40–42, 44, 75, 76, 78, 83–85, 89, 90, 93 Connective tissue mast cells, 17, 25, 91 Corticosteroids, 64 Cromolyn sodium, 43, 106 Cytotoxic drugs, 64

© Springer Nature Switzerland AG 2019 D. Ribatti, The Mast Cell, https://doi.org/10.1007/978-3-030-24190-2

D Dendritic cells, 7, 9, 40, 41, 60, 82 De-novo synthesized mediators, 36, 37 Development, 5–11, 26, 29–31, 44, 51–54, 59, 63, 67, 68, 71, 76, 77, 96, 103, 105, 106 Duodenum, 27, 28 E Eosinophilic granulomatosis with polyangiitis, 60–62 Experimental tumors, 91 F Fibrosis, 26, 36, 42–44, 59 G Gabexate mesylase, 105 Giant cell arteritis, 59, 61, 62 H Haematological tumors, 94 Heparin, 16, 17, 21, 25–27, 31, 37, 38, 44, 54, 75, 76, 82, 83, 90, 91 Histamine, 21, 25–27, 30, 31, 36–38, 41–44, 54, 63, 68, 69, 75–78, 82, 85, 90, 91, 106 Hypoxia, 51, 81, 82, 85, 105 I Imatinib mesylate, 104, 107 Inflammation, 9, 39–42, 44, 51, 54, 55, 59, 60, 63, 64, 68, 69, 75–78, 83, 94, 105 Inflammatory cells infiltrate, 25, 45, 59, 81 Innate immune response, 41

111

112 Integrin, 7, 9, 30, 53 Interleukin, 10, 37, 38, 42, 53, 68 K Kawasaki disease, 60–62 L Lymphangiogenesis, 82, 89, 96, 97 M Macrophages, 7, 30, 37, 41, 53–55, 59, 60, 63, 76, 81, 83, 86 Mammary gland, 29, 30 Mast cell deficient mice, 7, 9, 53, 62 Mast cell heterogeneity, 25, 26 Mast cells, 5–11, 15–21, 25–31, 35–45, 51, 53–55, 59, 62–64, 67–72, 75–78, 81–86, 89–97, 103–107 Matrix metalloproteases, 89 Metachromasia, 15–17 Microscopic polyangiitis, 60, 61 Mucosal mast cells, 5, 10, 11, 17, 25, 44 Multiple sclerosis, 43, 68–71 Myeloid progenitors, 7 O Organ microenvironment, 64, 81 P Polyarteritis nodosa, 60, 61 Preformed mediators, 26, 37 Proteases, 15, 19, 25, 26, 29, 30, 35–38, 44, 53, 54, 63, 75, 77, 78, 89, 93, 105, 106

Index S Safranin, 17, 18 Secretory granules, 17, 19, 35, 37, 39, 41, 91, 92, 94 Solid tumors, 81, 89, 93 Staining, 15–21, 75, 94 Stem cell factor, 8, 93 Steroids, 103, 106 Stroke, 52, 68–70 T Takayasu arteritis, 59–62 T cells, 10, 25, 26, 30, 40, 42, 43, 54, 59, 60, 62, 63, 69, 70, 77 Thymus, 5, 25, 27, 28 Tissue remodelling, 71, 72, 76, 78, 106 Tissue repair, 26, 44, 77 Toluidine blue, 15–17, 35 Tregs, 42, 43, 62, 82 Tryptase, 8, 19–21, 25–29, 31, 37, 38, 40–42, 44, 63, 64, 69, 75–78, 82–85, 89, 93, 94, 96, 104, 105 Tumor growth, 82, 94, 104–106 Tumor microenvironment, 81, 82, 103, 106 Tyrosine kinase inhibitors, 104 Tyrosine kinase receptor kit, 18, 103 V Vascular Endothelial Growth Factor (VEGF), 27, 37, 39, 42, 43, 51, 52, 54, 63, 70, 71, 76–78, 81, 82, 85, 91, 93, 94, 104, 105 Vasculitides, 59, 60–62, 64 VEGF-C, 37, 82, 96, 97