Mechanisms underlying the localisation of mast cells in tissues

Review

Innate immune cell trafficking

Mechanisms underlying the localisation of mast cells in tissues Sarah J. Collington1, Timothy J. Williams2 and Charlotte L. Weller2 1 2

Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK

Mast cells are tissue-resident cells best known for their role in allergy and host defence against helminth parasites. They are involved in responses against other pathogenic infections, wound healing and inflammatory disease. Committed mast cell progenitors are released from the bone marrow into the circulation, from where they are recruited into tissues to complete their maturation under the control of locally produced cytokines and growth factors. Directed migration occurs at distinct stages of the mast cell life-cycle and is associated with successive up- and downregulation of cell surface adhesion molecules and chemoattractant receptors as the cells mature. This article discusses some of the recent advances in our understanding of the mechanisms underlying mast cell recruitment. The importance of mast cell migration Mast cells are long-lived, tissue-resident cells that are enriched at boundaries of the body, such as the gastrointestinal mucosa, respiratory mucosa and skin. These distinctive granular cells are found in most other tissues, where they often associate with blood vessels and nerve endings. Mast cells are best known for their role in allergy, in which they mediate acute symptoms such as wheal and flare responses in skin conditions, bronchoconstriction in asthma, obstruction and mucus hypersecretion in allergic rhinitis, and life-threatening systemic anaphylaxis [1]. Mast cells play a role in host defence, in particular against helminth parasites: expulsion of certain nematodes, for example Trichinella spiralis, from the intestinal tract is mast cell-dependent in animal models [2,3]. Local host defence against bacterial, fungal and viral infections involves mast cells and they are equipped with a range of pattern recognition receptors, such as the Toll-like receptors (TLRs) 1–7 and 9, that facilitate the detection of foreign organisms and their products [4]. In addition, organisms that are recognised by the complement system can trigger mast cell responses: mast cells have receptors for C3a and C5a, peptide fragments that are generated during complement activation [5]. Directed migration is essential at several stages of the mast cell life-cycle including: (i) progenitor movement towards the sinusoids in the bone marrow; (ii) migration through the sinusoidal endothelium; (iii) recruitment via Corresponding author: Weller, C.L. ([email protected]).

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venules into tissues; and (iv) migration during maturation towards their final location within the tissue. Mechanisms operate under basal conditions to maintain mast cell numbers in tissues. In addition, local mast cell hyperplasia, a prominent feature of allergic reactions and responses to helminth parasite infection, is likely to involve increased progenitor recruitment in addition to increased local mast cell proliferation [6]. Therefore, the therapeutic targeting of the mediators and mechanisms that regulate mast cell progenitor recruitment during inflammation may reduce the number of mast cells recruited to the affected tissues and attenuate the subsequent effect of mast cell activation in these locations. There is no therapeutic agent that specifically targets mast cell migration, but a reduction of tissue mast cell numbers has been observed experimentally in allergy models in mice that are genetically deficient in phosphoinositide 3-kinases [7,8]. Furthermore, one of the indirect effects of the IgE-neutralising therapeutic antibody, omalizumab, in allergic patients is a reduction of tissue FceRI + cells, mainly mast cells [9]. Mast cells are thought to use the same basic migration mechanisms as other granule-containing inflammatory cells. Chemoattractant molecules generated in tissues recruit granulocytes by acting on surface receptors that activate integrins causing adhesion with complementary molecules on the venular endothelium [10]. Arrest of the leukocyte and its subsequent migration through the endothelium is regulated by coordinated adhesive interactions and cytoskeletal changes in the leukocyte [10]. Although the relevant molecules involved in the recruitment of different circulating leukocyte types has been delineated in detail, [11–14] the context of mast migration is different. Granulocytic leukocytes, neutrophils, eosinophils and basophils mature in the bone marrow and circulate with a short half-life in the blood from where they can be recruited into tissues on demand in response to an appropriate inflammatory stimulus. Mast cells, however, mature in peripheral tissues and committed progenitors are detected only in low numbers in the bone marrow and blood [15–17]. Once recruited to the tissues, mast cells mature under the influence of cytokines and growth factors in the local microenvironment [18,19]. The low number of mast cell progenitors in the bone marrow, blood and tissues makes it challenging to address their migratory mechanisms. In addition, the surface expression of molecules crucial for migration changes during cell maturation and

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Review differs depending on the phenotypic fate of the cell [6,20]. Thus, how mast cells migrate in vivo is poorly understood compared to other cell types. Nevertheless, piecing together in vitro and in vivo observations provides a growing understanding of mast cell migration. We describe here some of the key mediators that direct migration of mast cells during their life-cycle: mediators that operate in concert with successive up- and downregulation of cell surface adhesion molecules and chemoattractant receptors as the cells mature. Mast cell function, subsets and tissue localisation In allergy, IgE antibodies bind high-affinity FceR1 receptors on mast cells to initiate an allergen-specific response. Cross-linking of IgE by a specific allergen leads to mast cell degranulation and release of preformed mediators, such as histamine and TNF-a, as well as synthesis of acute mediators, such as leukotrienes and prostaglandins [4,21]. These mediators induce rapid responses, e.g. vasodilatation and microvascular leakage, by stimulating vascular smooth muscle and endothelial cells [22], contraction of gastrointestinal and bronchial smooth muscle [23–26], and stimulation of mucus glands and afferent nerve endings [26,27]. The acute effects are followed by the synthesis of cytokines and growth factors, for example, IL-5, IL-13, and TNF-a. Some of the mediators produced by mast cells (e.g. metabolites of arachidonic acid, and chemokines) stimulate the recruitment of other inflammatory cells, such as neutrophils, eosinophils and T lymphocytes, from the blood microcirculation to amplify the local inflammatory reaction [28–31]. Mast cell-derived mediators can induce dendritic cell maturation and migration to regional lymph nodes [32,33]. Mast cell responses and the secretory products generated are tailored to the stimulus and the particular cell surface receptors engaged [34]. For example, viruses or double-stranded RNA stimulate TLR3 to induce IFN-a production from human mast cells in the absence of degranulation and secretion of IL-1b and GM-CSF [35]. By contrast, TLR2 ligands, such yeast cell wall, induces mast cell IL-1b and GM-CSF production, which can be associated with degranulation and LTC4 secretion, depending on the ligand [36]. In the mouse, there are two main mast cell subtypes: mucosal mast cells that are associated with the epithelium of the lung and gastrointestinal tract, and connective tissue mast cells that are found in the intestinal submucosa, peritoneum and skin. Intestinal mucosal mast cells are characterised by expression of the chymases mMCP-1 and mMCP-2, whereas connective tissue mast cells express the chymase mMCP-4, an elastinolytic enzyme (mMCP-5) and two tryptases (mMCP-6 and mMCP-7) as well as carboxypeptidase A [37,38]. Mucosal mast cells have low histamine content, but produce large amounts of cysteinyl leukotrienes, whereas connective tissue mast cells have a higher histamine content and produce high levels of prostaglandin D2 [39]. There are two main mast cell subtypes in man; those containing chymase and tryptase (MCTC) and those containing tryptase alone (MCT) [38]. In the human lung, MCT are more prominent in the bronchi, bronchioles and alveolar parenchyma, although a subtype of severe asthmatics has recently been shown to have high numbers

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of MCTC that are associated with airway epithelium, corresponding with large amounts of prostaglandin D2 [40]. These different subtypes of mast cells are thought to express specific adhesion molecules and chemoattractant receptors that facilitate their differential localisation. Even within the same tissue, there can be considerable phenotypic mast cell plasticity. In naive mice, for example, most jejunal mast cells reside in the submucosa and express mMCP-6 and mMCP-7, but not mMCP-9 or the chymase mMCP-2. During the inductive phase of Trichinella spiralis infection, the jejunal mast cells migrate from the submucosa to the tips of the villus, downregulate mMCP-6 and -7 and briefly express mMCP-9, before upregulating mMCP-2. During the recovery phase of the inflammation, jejunal mast cells downregulate mMCP-2 and upregulate mMCP-6, mMCP-7 and mMCP-9 as they move from the tips of the villus back toward the submucosa [41]. Mast cells can be stimulated to release a plethora of proand anti-inflammatory mediators and regulation of mast cell localisation is therefore paramount. Molecules and mechanisms that regulate the appropriate localisation of mast cells in a tissue are discussed in the following sections. Tissue-specific recruitment of mast cells by adhesion molecules Cell migration involves the detection of a chemoattractant signal by surface-expressed receptors and sequential upregulation and downregulation of adhesion molecules coordinated with cytoskeletal changes in the cell. Specific adhesion molecules on the cell surface enable the circulating cell to attach to specialised regions of microvascular endothelium, to move through tissues and to sense and become localised in particular regions of tissues. Early studies of neutrophils demonstrated that recruitment via venules involves loose tethering to the endothelium to induce leukocyte rolling that is mediated by interactions between selectin molecules and their glycoprotein ligands [42]. Chemoattractants then signal via specific receptors on the leukocyte to upregulate integrins that bind complementary molecules on the endothelium to induce firm binding. This is followed by migration through the endothelium [43]. The small number of progenitors in the circulation precludes such studies with mast cells in vivo, but the behaviour of cultured mouse bone marrow-derived mast cells (BMMCs) when injected intravenously into mice is similar to that of neutrophils, as observed by intravital microscopy [44]. The integrin a4b7 is involved in mast cell progenitor homing to the gut through interaction with the adhesion molecules mucosal addressin cell adhesion molecule-1 (MAdCAM-1) or vascular cell adhesion molecule-1 (VCAM-1) on the endothelium [45]. Thus, b7-deficient mice have reduced numbers of progenitor and mature mast cells in the gut [45]. In the lung, the integrins a4b1 and a4b7 interact with VCAM-1 and are important for mast cell recruitment in a model of allergic airways disease [46,47]. The a4b7 integrin is expressed by BMMCs, but is downregulated during maturation [6]. Other integrins have a role in vivo; aIIbb3 deficiency results in reduced peritoneal mast cell numbers [48] and amb2 deficiency reduces numbers in the peritoneal cavity, peritoneal wall and skin [49]. There is evidence that mature mucosal mast cells are able to localise 479

Review in the gut epithelium utilising aE integrin, which attaches to E-cadherin at epithelial junctions [50]. Thus, specific integrins control recruitment of mast cells to different tissue locations depending on the inflammatory state. How the expression of these molecules changes as mast cells mature and transit from the peripheral blood into their final tissue location is not fully understood. Direct and indirect recruitment of mast cells by chemokines Chemokines have an important role in recruitment of granulocytes and provide some cell-type specificity; e.g. IL-8 and eotaxins in neutrophil and eosinophil recruitment, respectively. These mediators are able to release mature cells from the bone marrow; e.g. eotaxin-1 induces eosinophil release [12,51]. Under certain conditions, immature forms of granulocytes are released from the bone marrow in addition to mature cells, e.g. eotaxin-1 can release eosinophil progenitors [12] and these cells are able to mature in tissues. Eosinophils, like mast cells, are resident cells under basal conditions in intestinal tissues. Although mouse and human cultured mast cells express several chemokine receptors and respond to chemokines in chemotaxis assays in vitro [52] no mast cell-specific chemokine has emerged and it has proved difficult to assign a specific role for chemokines in mast cell trafficking in vivo. Human cultured mast cells express CXCR2, CXCR4, CX3CR1, CCR3 and CCR5 receptors in vitro and respond to chemokine ligands in chemotaxis assays [20,53–56]. During mast cell maturation, only expression of CCR3, the receptor for CCL11, CCL24 and CCL26 (eotaxin-1, -2 and -3) is maintained [20], suggesting a role for CCR3 in tissue localisation. However, CCR3-deficient mice infected with Trichinella spiralis have normal mast cell numbers in the skin [57]. In allergen-induced lung inflammation, the numbers of mast cell progenitors in the lung are comparable between CCR3-deficient and wild type mice [47]. Furthermore, mature mast cells in the trachea are increased in the CCR3-deficient mice in this model [58]. In vitro, mouse BMMCs express Ccr3 mRNA, but surface expression of receptor is not detected and the cells do not respond chemotactically to CCL11 [59]. These data highlight some of the difficulties in the mast cell field, with contrasting observations from in vitro and in vivo experimental systems. For CCL11, these differences may be reconciled with data suggesting that the CCL11 CCR3 axis may be more involved with mast cell development, rather than migration [60]. This is highlighted by the finding that immediate hypersensitivity reactions in the conjunctiva are ablated in mice deficient in CCL11, despite normal numbers of tissue mast cells and concentration of IgE. In addition, evidence that CCL11 acts in a synergistic manner with stem cell factor (SCF) to increase embryonic mast cell progenitor numbers has been described [61,62]. Limiting dilution assays have been used to overcome some of the challenges associated with the low numbers of mast cells in vivo, and have provided valuable information about mast cell progenitor numbers in mouse tissues [45]. This technique can estimate the number of mast cell progenitors in a particular tissue. Isolated tissue mononuclear cells, which contain mast cell progenitors, are 480

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serially diluted in mast cell-specific medium to expand and mature mast cells, which are then enumerated to estimate mast cell progenitor numbers in the mononuclear population. Such studies show that CXCR2 contributes to recruitment of mast cell progenitors to the lung: it appears that expression on the lung stromal cells, rather than on the progenitors, is important and the authors suggest that CXCR2 directly controls VCAM-1 expression on the endothelium. Increased CXCR2 expression leads to elevated VCAM-1 expression, facilitating increased a4b7 integrinmediated mast cell progenitor recruitment to the lung [47]. The receptor CCR2 is expressed on BMMCs and its ligand, CCL2 (MCP-1), has been detected in allergen-challenged lung. The elevation in CCL2 was associated with increased mast cell numbers [63]. In vitro, CCR2 is coupled to the signalling pathways mediating chemotaxis only if the cells are cultured with SCF in addition to IL-3, suggesting a role for SCF in regulation of CCR2-mediated chemotaxis [63]. Although CCR2- and CCL2-deficient mice have reduced mast cell numbers in the allergen-challenged lung, similar to CXCR2, receptor and ligand expression appears to be important on the lung stromal cells, rather than on the mast cells. The specific mechanism by which these molecules regulate trafficking of mast cell progenitors needs further investigation and it is not yet known whether CCR2 expression is linked to expression of any adhesion molecules as seen for CXCR2. [63]. These studies have expanded our understanding of the role of chemokine receptors on the microvascular endothelium in directing mast cell migration. CXCR3 might also be important for mast cell localisation within tissues. Synovial mast cells exhibit high expression of CXCR3 in patients with rheumatoid arthritis and the ligands for CXCR3, CXCL9 and CXCL10, are expressed in synovial tissue. Thus, CXCR3 and its ligands might mediate mast cell recruitment to the synovium in rheumatoid arthritis [64]. A potentially important story has also emerged in asthma. Mast cells localise within airway smooth muscle tissue bundles in asthmatic patients [65]. In addition, human airway mast cells express the CXCR3 receptor, and migrate in response to CXCL10 in vitro and this chemokine was shown to be expressed in asthmatic airway smooth muscle [66]. The multiple chemokines and receptors described here function in directing mast cell homing and trafficking in different disease settings, illustrating the tight regulation of mast cell localisation. However, no mast cellspecific chemokine has been observed to date. A variety of molecules can enhance or inhibit chemokine-mediated migration. Chemotaxis-potentiating factors, many of which induce increased random migration, have been identified for other cell types; e.g. IL-5 and histamine enhance eotaxin-induced migration of eosinophils [12,67]. Histamine also enhances CXCL12 (SDF-1a)induced in vitro migration of human mast cell precursors, which is mediated by the H4 receptor, as shown using selective H4 receptor antagonists [68]. By contrast, progesterone inhibits mast cell migration to CXCL12 by reducing expression of CXCR4 [69]. These findings raise the possibility that gender and post-menopausal state influence mast cell infiltration into tissues and illustrate the complexity of mast cell trafficking regulation.

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Lipid mediators contribute to mast cell recruitment during inflammation Repeated exposure to allergen in sensitised individuals results in a marked mast cell hyperplasia; e.g. as is seen in the lung epithelium, mucus glands and airways smooth muscle of asthmatic patients and in the nasal mucosa of patients with allergic rhinitis [65,70–74]. The underlying mechanism may involve activated mature mast cells in the tissue releasing mediators that recruit progenitors from the circulation. Cytokines and growth factors in the inflamed tissue could then induce proliferation and maturation of mast cells, which migrate along local gradients in the tissue to their final destination; e.g. the airway epithelium. In line with this, secretory products from mature BMMC activated by IgE cross-linking induce chemotaxis of 2–3 week old immature BMMCs. Chemotaxis was mediated by leukotriene B4 (LTB4), as identified by HPLC purification and mass spectrometry [6]. Although LTB4 was potent on immature cells, chemotactic activity was lost as the cells matured, correlating with the loss of mRNA for the high affinity receptor, BLT1. Immature BMMC, when injected intravenously, accumulated in vivo in response to intradermally injected LTB4 in mice. Mast cell progenitors in a suspension of cells in freshly isolated bone marrow were tested in chemotaxis assays against LTB4 in vitro. Migrated cells were matured with mast cell-specific cytokines, lysed and mast cell-specific proteases mMCP-1 and mMCP-2 measured. These experiments demonstrate that mast cell progenitors respond chemotactically to LTB4 [6]. Similar results were obtained with human cultured cord blood-derived mast cells, where only immature mast cells responded chemotactically to LTB4 [6]. These experiments suggest that LTB4 may be important for recruiting mast cell progenitors to tissues, but that other mediators may be

involved in localisation of the mast cells within the tissues as they mature (Figure 1). Another approach to examine the mechanisms mediating mast cell progenitor recruitment utilised allergen-challenged mucosal tissue as a potential source of mast cell chemoattractants [75]. Nasal mucosal tissue from sensitised mice was exposed multiple times to allergen to induce mast cell hyperplasia in vivo. The mucosa was removed and incubated to produce conditioned medium, which was then shown to exhibit chemotactic activity against immature BMMCs in chemotaxis assays. HPLC and mass spectrometry identified the chemotactic factor as prostaglandin E2 (PGE2), signalling through the EP3 receptor [75]. Some of the components of the signalling pathways involved in this novel activity of PGE2 (better known as a vasodilator mediator) have been delineated recently [76]. There were interesting differences between the activity of PGE2 and LTB4. PGE2 was inactive as a chemotaxin on mast cell progenitors, but was active on 2–3 week old immature and 10 week old mature mast cells [75]. Thus, PGE2, which has been shown to be active on human mast cells [77], may be involved in mast cell localisation within tissues, rather than in the recruitment of progenitors from the microcirculation where LTB4 appears to be more important (Figure 1). PGE2-induced mast cell migration can be further regulated in the presence of other mediators. For example, antigen-induced activation of FceR1 on BMMC enhances chemotaxis in response to PGE2, as well as SCF and adenosine [76]. Simultaneous challenge of mast cells with antigen and specific GPCR ligands, such as PGE2, resulted in activation of signalling pathways leading to the integrated activation of PI3Ks with an associated synergistic activation of membrane-associated Btk and enhanced mast cell chemotaxis [76]. The results of this study

Airway epithelium Mature mast cell PGE2

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Figure 1. Lipid mediators in mast cell trafficking. Mast cells are released from the bone marrow as committed mast cell progenitors and circulate in the peripheral blood until they are recruited into the tissues where they differentiate terminally under the control of growth factors in the local microenvironment. The chemoattractant LTB4 is released very early in allergic responses as mast cells release LTB4 upon IgE-mediated activation. LTB4 is thought to be important for recruiting mast cell progenitors to tissues, acting via the high-affinity LTB4 receptor BLT1. As these mast cell progenitors mature, they downregulate BLT1 and become unresponsive to LTB4. In contrast to LTB4, the PGE2/EP3 axis mediates mast cell localisation within tissues, rather than the recruitment of progenitors.

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Bone marrow progenitor

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α4β7 integrin expression

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Figure 2. Key mediator responsiveness and integrin expression during in vitro mast cell development. The kinetics of expression of the key chemoattractant and adhesion molecules during maturation of mouse bone marrow-derived mast cells in vitro, and how this could relate to mast cell localisation in vivo. LTB4 and CCL2 are important chemoattractants for recruiting mast cell progenitors to tissues acting via the cellular receptor BLT1 and CCR2, respectively. In contrast, PGE2 and SCF mediate mast cell localisation within the tissue, which is controlled by the subsequent up- and downregulation of their cellular receptors. The integrin a4b7 is expressed on only very immature cells and therefore probably aids in the initial trafficking of mast cell progenitors before it is rapidly downregulated as these cells mature.

demonstrate a potential mechanism by which signalling through receptors from several classes may integrate to promote migration of mast cells into tissues in an inflammatory setting. Growth factors and cytokines in mast cell recruitment In general, growth factors and cytokines are not directly chemotactic for mast cells, but promote mast cell growth and development. Exceptions to this are the growth factor SCF, which has chemotactic and regulatory effects on mast cell trafficking, as well as several cytokines that indirectly affect mast cell migration. SCF is crucially important for mast cell function. Mice deficient in SCF, or its receptor, c-kit, lack tissue mast cells. Reconstituting these mice with wild type BMMC or BMMC that are deficient in specific molecules has allowed the effect of mast cell mediators in different inflammatory settings to be dissected [78,79]. In addition, SCF is chemotactic for mouse [80] and human [81] mast cells in vitro. This is mediated by c-kit, a tyrosine kinase receptor in contrast to the majority of other chemotactic mediators described in this article which are 7-transmembrane, G protein-coupled receptors. c-kit is expressed by mast cell progenitors, and immature and mature mast cells. However, mast cell progenitors from bone marrow freshly isolated from mice are unresponsive to the chemotactic effects of SCF, whereas cultured 2–3 week immature and 10 week mature BMMC responded to SCF in chemotaxis assays [6]. Further, chemotaxis in response to SCF did not occur in immature c-kitlow cells isolated from human cord blood, but a prominent response was observed in more mature c-kithigh cells [6]. This suggests that SCF is not involved in progenitor recruitment to tissues, and that coupling of the c-kit receptor to the chemotaxis machinery in mast cells is related to cellular migration along chemotactic 482

gradients during maturation within tissues (Figure 2). More recent data suggest that SCF can also regulate chemotaxis stimulated by CCR2, possibly via the accessory protein FROUNT [63]. The cytoplasmic adaptor molecule, FROUNT, is essential for CCR2-mediated migration of a CHO cell line [82] and mesenchymal stem cells [83]. In these cells, CCL2 binding to CCR2 induced translocation of FROUNT which bound to CCL2–CCR2 complexes at the leading edge of the migrating cell, allowing receptor clustering and a link to the PI3K-Rac-lamellipodium protrusion cascade [82,83]. This mechanism could occur in mast cells and requires further investigation. There is some evidence that cytokines can both positively and negatively regulate mast cell migration. The expression of the Th1-specific transcription factor T-bet by dendritic cells was shown to be essential for mast cell progenitor homing to the lung and intestines using T-bet-deficient mice [84]. However, the mechanism and the specific mediators regulating this effect remain to be established. Mast cell progenitor recruitment in BALB/c mice is prevented by blockade of CD4+ cells during challenge using a monoclonal antibody [85]. Studies with genetically deficient mice and monoclonal antibodies ruled out a role for Th2 cells, but revealed a role for IL-9 and CD1d-restricted NKT cells in mast cell progenitor recruitment to the antigen-challenged lung [85]. A subsequent study using C57BL/6 mice, showed that CD1d-restricted NKT cells and IL-9 do not have a role in antigen-induced mast cell progenitor recruitment; however, CD25+ T regulatory (Treg) cells and their associated cytokines TGF-b1 and IL-10 were involved in this strain [86,86]. Thus, despite the similar fold increase in mast cell progenitor numbers in the lung 3 days after antigen challenge, mechanisms of CD4+ T cell-mediated regulation of mast cell progenitor recruitment are mouse strain-dependent. IL-10 has a well-defined role as an immunomodulatory cytokine

Review and its production by mast cells can limit the progression of inflammatory disorders (reviewed in [87]). IL-10 affects mast cell development, survival and function [88,89] and was shown to inhibit TNF-a, RANTES and NGF-induced migration of mature mast cells [90]. In this capacity, IL-10 may reduce the inflammatory response, in part, by limiting mast cell migration in tissues [90]. As well as molecules that directly induce trafficking of mast cells, it is becoming clear that the regulation of these chemoattractant molecules is crucial to the final localisation of these cells. Concluding remarks As tissue-resident cells in a prime location to detect inflammatory signals, mast cells have an important role in initiating and perpetuating inflammatory responses that are central to host defence and tissue repair after injury. To this end, the appropriate localisation of these cells is paramount. The mechanisms underlying localisation are complex and challenging to study because low numbers of progenitors are recruited to tissues and, as the cells proliferate and mature, their surface expression of chemoattractant and adhesion molecules changes to effect their migration into the tissue. The nature of these expressed molecules differs depending on the tissue, and the cytokines and growth factors generated in the local microenviroment that determine the phenotype of the mature mast cell. None of the mediators thought to be involved in the recruitment of mast cell progenitors are specific for this cell type, so presumably local cytokines and growth factors determine which of the recruited cells survive in the tissue. There is increasing knowledge about the role of mast cells in pathophysiology [91,92]. Detailed studies on mechanisms of mast cell localisation will further this knowledge and provide opportunities for the discovery of novel therapeutic agents aimed at reducing tissue mast cell numbers and the associated pathology in diseases such as asthma and allergy. References 1 Weller, C.L. et al. (2011) Mast cells in health and disease. Clin. Sci. (Lond.) 120, 473–484 2 Ha, T.Y. et al. (1983) Delayed expulsion of adult Trichinella spiralis by mast cell-deficient W/Wv mice. Infect. Immun. 41, 445–447 3 Lawrence, C.E. et al. (2004) Mouse mast cell protease-1 is required for the enteropathy induced by gastrointestinal helminth infection in the mouse. Gastroenterology 127, 155–165 4 Galli, S.J. and Tsai, M. (2010) Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity. Eur. J. Immunol. 40, 1843–1851 5 Ali, H. (2010) Regulation of human mast cell and basophil function by anaphylatoxins C3a and C5a. Immunol. Lett. 128, 36–45 6 Weller, C.L. et al. (2005) Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors. J. Exp. Med. 201, 1961–1971 7 Ali, K. et al. (2004) Essential role for the p110delta phosphoinositide 3kinase in the allergic response. Nature 431, 1007–1011 8 Koyasu, S. et al. (2005) The role of phosphoinositide-3-kinase in mast cell homing to the gastrointestinal tract. Novartis Found. Symp. 271, 152–161 (discussion 161–165, 198–199) 9 Holgate, S. et al. (2005) The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J. Allergy Clin. Immunol. 115, 459–465 10 Ley, K. et al. (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689

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