Review                           TRENDS in Immunology            Vol.28 No.5

Mast cells – key effector cells in
Review                       TRENDS in Immunology          Vol.28 No.5                                                    ...
236                     Review                         TRENDS in Immunology Vol.28 No.5

Table 2. Novel protective mast ...
Review                TRENDS in Immunology    Vol.28 No.5                                                          237

238                     Review         TRENDS in Immunology Vol.28 No.5

responses towards Th1. Indeed, skin MCs proved ...
Review         TRENDS in Immunology    Vol.28 No.5                                                                 239

240                     Review                    TRENDS in Immunology Vol.28 No.5

20 Maurer, M. et al. (2004) Mast cel...
Review                    TRENDS in Immunology         Vol.28 No.5                                                        ...
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Mast cells – key effector cells in immune responses


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Mast cells – key effector cells in immune responses

  1. 1. Review TRENDS in Immunology Vol.28 No.5 Mast cells – key effector cells in immune responses Martin Metz1,2 and Marcus Maurer1 1 Department of Dermatology and Allergy, Charite – Universitatsmedizin Berlin, 10117 Berlin, Germany ´ ¨ 2 Department of Pathology, Stanford Medical School, Stanford, CA 94305, USA Mast cells are best known for their potent effector with the environment, that is, the skin, gut and airways functions in allergic disorders. In recent years, however, [3]. Although this could be for various reasons, the most mast cells have been identified to be involved in a probable explanation for this remarkable distribution is surprisingly complex range of immune functions that that these tissues are primary target sites for infection go far beyond allergies and include the development of with bacteria, viruses and parasites. Interestingly, MC autoimmune disorders and peripheral tolerance, and the populations of the skin exhibit two unique gradients of initiation and maintenance of adaptive and innate host distribution in that cutaneous MC numbers increase (i) responses. Here, we review the key signals and effector with proximity to the epidermis and (ii) with distance from mechanisms that have lately been identified for mast cell the center of the body [11]. In other words, the most functions in these immune responses. superficial layers of hand, feet and facial skin, where the risk of bacterial infection is the highest, contain markedly Introduction more MCs than deep layers of truncal skin, where the risk Mast cells (MCs) have long been recognized for their of infection is lowest. detrimental role in the elicitation of allergic symptoms. Differences in the concentrations of stem cell factor (SCF) They are considered to be one of the main culprits in acute and certain other cytokines and chemokines, for example, allergic diseases, and there is continuing strong research in interleukin (IL)-3, IL-2, IL-4, IL-9, IL-18, monocyte che- this field focusing mainly on the signaling events following moattractant protein (MCP)-1, RANTES or nerve growth allergic MC activation [1,2] and on the role of MCs in factor (NGF) in the respective tissues, and possibly even chronic allergic diseases in addition to their possible func- between different sites within the same tissue, can deter- tion as negative regulators of allergic responses [3]. How- mine the number, distribution and phenotype of MCs at that ever, in recent years, MCs have been identified as being site [3,5,12–14]. This flexibility (generally referred to as ‘MC responsible for a far more complex range of functions. heterogeneity’) enables them to respond adequately to These new findings further expand our knowledge on diverse physiological, immunological, inflammatory or ot- MCs beyond their functions in allergic reactions as we her signals that MCs encounter at their respective location. now know that they are also involved in the development of autoimmune diseases such as multiple sclerosis, bullous Mast cell activation pemphigoid and rheumatoid arthritis [4], and that they MCs are best known for their prominent role in allergic also contribute to peripheral tolerance [5] and adaptive diseases and, therefore, ‘allergic activation’ through IgE and innate immune responses [6–8]. This review will high- bound to high affinity IgE-receptor (FceRI) expressed on light the recent advances in the understanding of nonal- the MC surface is the best studied mechanism of MC lergic functions of MCs, focusing on the important role of activation [1,15]. However, numerous other immunological MCs as effector cells in immune responses to pathogens. and non-immunological signals can lead to the activation of MCs; for example, some MCs can be activated by IgG Mast cell effector functions – leads from basic through the Fcg receptor, by various cytokines, chemo- mast cell biology kines, endogenous and exogenous peptides, chemical There is some controversy about the developmental agents or physical stimuli [2,6]. Overall, a surprisingly pathway that leads to the generation of committed MC large number of biological substances have been shown progenitors in adult mice. Arinobu and colleagues propose to activate MCs, and many of these substances are linked a bipotent basophil–MC progenitor [9], whereas Chen et al. to innate immune responses (Table 1). For example, bac- describe a committed MC progenitor, which they identified teria and bacterial products, viruses, bacterial and viral in the bone marrow of adult mice [10]. However, there is no superantigens, products of complement activation, com- argument that mature MCs are not detectable under ponents of animal venoms and peptides that are upregu- physiologic conditions in the circulation but instead ma- lated after infection with pathogens have all been shown to ture within the tissues in which they ultimately reside. induce the secretion of MC mediators [7,16–21]. Mature MCs can be found in almost every tissue but they are preferentially localized in organs that are in contact Mast cell mediators Corresponding author: Maurer, M. ( MCs have the ability to release a huge amount of diverse Available online 2 April 2007. biologically active mediators. These MC products can be 1471-4906/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/
  2. 2. Review TRENDS in Immunology Vol.28 No.5 235 Table 1. Mast cell activating signals in innate and adaptive immunitya Innate Immune Responses Adaptive Immune Responses Target Activating signal Target Activating signal Bacteria Escherichia coli FimH ! CD48 Bacteria ? [7,63,64] Toxins ! pore formation PGN ! TLR2 LPS ! TLR4 Complement ! CR1, CR2, CR3, C3aR, C5aR ET-1 ! ETA Ig-binding exogenous bacterial superantigens (e.g. Staphylococcus aureus protein A, Peptostreptococcus magnus protein L) Virus Double-stranded viral RNA ! TLR3 Virus [65] For example, RSV-specific IgE ! FceRI [7,64] Single-stranded viral RNA ! TLR7 Ig-binding endogenous viral superantigens (e.g. protein Fv in HBV und HCV) Parasites Schistosoma mansoni cercariae Parasites [66] For example, Haemaphysalis longicornis [64] Living Leishmania major promastigotes tick-specific IgE ! FceRI UVB Cis-urocanic acid Type-I IgE crosslinking ! FceRI [67,68] ET-1 ! ETA allergens [69] Monomeric IgE ! FceRI Animal venoms Mastoparan (from wasps), MCDP (from honeybee) or Type-IV allergens ? [21,52] natriuretic peptides ! direct activity through G proteins Sarafotoxins ! ETA Autoantigens For example, BP180-specific IgE ! FceRI Phospholipase A2 [70,71] For example, IgG1 ! FcgRIII a Abbreviations: BP, bullous pemphigoid; CR, complement receptor; MCDP, mast cell-degranulating peptide; PGN, peptidoglycan; RSV, respiratory syncytial virus. divided into two major categories: (i) preformed mediators the mechanism of activation and the strength of the signal, such as histamine, proteoglycans and neutral proteases, MCs release mediators of both categories (e.g. in IgE- and certain cytokines, for example tumor necrosis factor mediated MC degranulation) or they secrete distinct sub- (TNF), that are stored within the cytoplasmic MC granules sets of mediators with specific functions [25] (Figure 1). and that are released immediately after activation; and (ii) Products from both categories are important in innate mediators that are newly synthesized following activation, immune responses but, in particular, instantly released for example numerous cytokines, chemokines, lipid MC products seem to be crucial for initiating efficient mediators, and growth and angiogenic factors, which can immune responses at sites of infection (Table 2). mediate various proinflammatory, anti-inflammatory and/ The best-studied MC-derived product in the context of or immunoregulatory effects [3,6,18,22–24]. Depending on innate immunity is TNF, which induces the early influx of Figure 1. Mast cells can be activated to release preformed and/or de novo-generated products. The secretion of mast cell products can have numerous effects on other cell types and on pathogens and endogenous and exogenous peptides, which can lead to improved innate and/or acquired immune responses.
  3. 3. 236 Review TRENDS in Immunology Vol.28 No.5 Table 2. Novel protective mast cell-mediated effector mechanisms in immune responses Mast cell-derived signal Beneficial effector function a Tumor necrosis Optimal initiation of adaptive immune response after bacterial infection through recruitment factor of T cells to draining lymph nodes [54] b Optimal initiation of adaptive immune response by activating T cells [72,73] c Optimal adaptive immune response by inducing lymph node hypertrophy [54] b Optimal initiation of adaptive immune response by inducing Langerhans cell migration [55] b Decreased parasitemia and mortality [38] d Proteases Carboxypeptidase A enhances protection against snake venoms by reducing the toxicity of snake venoms [21] d Chymase and/or other proteases promote homeostasis by limiting the toxicity of toxic endogenous peptides (e.g. endothelin-1) [20] d mMCP-1 promotes the expulsion of nematodes by degradation of the tight junction protein occludin [28] d Leukotriene B4 Optimal immune response by recruitment of effector T cells [74] c Improving immune response by increasing mast cell numbers through recruitment of immature mast cells and/or mast cell progenitor [75] c Cathelicidin Reduction of bacteria numbers by direct bactericidal activity [37] c a Some of the mediators listed here have other effects that might be detrimental. b Mechanism proven (in vivo). c Possible mechanism (in vitro). d Mechanism and biological relevance proven (in vivo model). neutrophils, resulting in the clearance of pathogens and, arachidonic acid have also been implicated in improving consequently, in improved survival and/or morbidity innate host responses mainly by recruiting proinflamma- [17,18,26]. However, the largest group of preformed MC tory cells. They could also have a role in modulating the MC mediators is the proteases, which have recently received mediator release process itself [7,29,30]. increased attention in many areas of MC biology and particularly in investigations of innate responses. The Role of mast cells in innate immune responses to three major families of MC proteases (the serine proteases bacteria chymase and tryptase and the metalloprotease carboxy- Since their discovery, MCs have been hypothesized to exert peptidase A) constitute the major protein component of MC beneficial innate immune functions. For example, MCs secretory granules and, therefore, it is not surprising that have long been thought to phagocytose pathogens and the rapid release of proteases in innate immune responses to contribute to local ‘detoxification’ [26]. Nowadays, is associated with improved host defense and/or increased MC-deficient mouse models enable the identification and survival, for example by enhancing resistance to parasites characterization of the contribution of MCs to any bio- and by degrading endogenous or exogenous toxic peptides logical response of interest through the analysis of exper- [20,21,27,28] (Figure 2). imental outcomes in MC-deficient mice, the corresponding Among the de novo synthesized substances, wild-type mice and MC-deficient mice that have been lipid-derived mediators such as cyclooxygenase (prosta- selectively repaired of their MC deficiency by the local glandins) and lipoxygenase (leukotrienes) metabolites of engraftment of MCs [31–33]. Figure 2. Major murine mast cell proteases and their potential effector functions in vivo. Following appropriate activation, mast cells release a variety of proteases with diverse potential effector functions in vivo. It is important to note that the protease content can vary considerably depending on the maturation status of MCs, their tissue localization and the genetic background of the mice. Some proteases have as yet no known functional role but it is expected that new or additional physiologic and/or pathogenic functions will be discovered for these and other proteases in the near future. Chymases are indicated by *, and tryptases are indicated by #. References are given in parentheses.
  4. 4. Review TRENDS in Immunology Vol.28 No.5 237 Using this so-called ‘MC knock-in mouse’ model, and, among other factors, dependent on its site, kinetics Echtenacher and Malaviya and their respective co-workers and the bacteria involved. For example, in acute septic showed that MCs are crucial cells for the elicitation and peritonitis, endothelin (ET)-1 is a major MC activator that development of optimal innate host responses and for results in the degranulation of MCs and the subsequent survival in mice during septic peritonitis and other bac- release of preformed and granula-stored mediators, includ- terial infections [34,35]. Following these two seminal ing proteases, which then can reduce the concentrations of reports, the mechanisms by which MCs exert their protec- toxic peptides. Conversely, other signals that can activate tive effects in innate immune responses have been studied MCs during innate immune responses to bacteria, for extensively. We now know that MCs can provide protection example through Toll-like receptors (TLRs), do not induce only after being activated, and that MC activation in the MC degranulation but induce the secretion of selective context of innate immune responses can result from both cytokines and/or chemokines that can contribute to pathogen and host-derived signals. The latter include optimal host defense, for example through neutrophil activated complement products and endogenous peptides, recruitment [7,25] (Figure 1). both of which are produced rapidly in large amounts following bacterial infection [7,17,20,29]. Role of mast cells in innate immune responses to One crucial consequence of the activation of MCs in parasites response to bacterial infection and the subsequent secre- Parasite infections often induce strong primary and tion of their mediators, for example TNF or leukotrienes, is secondary IgE responses, and it has long been thought the optimal recruitment of inflammatory cells such as that MCs contribute to host defense against parasites by neutrophils [7,26,29]. However, MCs not only coordinate the immunological activation through FceRI. Studies in the influx of cells that subsequently eliminate pathogens MC-deficient mice have indeed shown that MCs can con- and, thus, improve the overall pathology and survival but tribute significantly to the expulsion of certain parasites are themselves effector cells in innate immune responses [7]; however, the exact mechanisms by which MCs mediate (Figure 1). For example, in vitro studies have shown that this protection was less clear. Recent reports have tried to MCs can phagocytose bacteria [36], and that they express address this question in different disease models. Two and secrete antimicrobial peptides that can eliminate studies using murine nematode infection models have pathogens [37]. However, their low numbers (e.g. <5% of demonstrated that MC numbers are increased in the skin cells and peritoneal cells) and their limited mobility intestinal mucosa during infection, and that MC activation and proliferative capacity, at least with respect to connec- during infection results in the release of the chymase tive tissue MCs, argue somewhat against a major role for mouse mast cell protease (mMCP)-1 [12,28]. The release direct bactericidal MC action, and the in vivo relevance of of mMCP-1 can contribute to the expulsion of the nema- these mechanisms has yet to be determined. Nevertheless, todes [27,28] by disrupting the epithelial barrier through the additive effects of these mechanisms might, to some degradation of the tight junction protein occludin [12,28] extent, contribute to the control of bacterial infections. (Table 2). MCs were also found to control infection in a Overall, MC activation during early innate immune malaria mouse model, and this effect was, at least in part, responses to pathogenic bacteria generally helps to limit dependent on TNF released from MCs [38]. More recently, the pathology associated with infection, which can largely it was reported that skin MCs in mice control T cell- be attributed to the contributions of MC mediators to dependent host defense in Leishmania major infections optimal host defense (Table 3). The mechanisms by which [39]. In addition to controlling and containing parasites at MCs elicit these protective effector functions are diverse the site of cutaneous infection, MCs were found to be and greatly shaped by the type and, possibly, the strength crucial for priming T cells, recruiting dendritic cells and of the activating signal, which, in turn, is infection-specific T cells to the site of infection, and for skewing cytokine Table 3. Novel findings of pathophysiological conditions in which mast cells have a role Condition Pathophysiological setting Mechanism of action Infection Bacteria (e.g. Group A Streptococcus, Bactericidal activity [37] Mycoplasma pulmonis) Contribution to containment of and recovery from lung infection [76] Initiation of protective adaptive immunity [54] Viruses (e.g. Newcastle disease virus) Recruitment of CD8+ T cells to site of infection [77] Parasites (e.g. Leishmania major, Improved expulsion [28] Plasmodium berghei, Trichinella Induction of adaptive immunity [39] spiralis) Release of TNF [38] Autoimmunity Experimental autoimmune Promotion of encephalitogenic Th1 responses by releasing IL-4 [78] encephalomyelitis Contribution to inflammation by production of IL-1 [79] Rheumatoid arthritis Promotion of remodeling and repair functions [80] Glomerulonephritis Influx of effector T cells and macrophages [81] Neoplasm Basal cell carcinoma Possible contribution to tumorigenesis by activation through Colonic epithelial tumors CD30 ligand [82] Promotion of tumor development [83] External hazards Wound healing Promotion of normal wound healing by releasing histamine [84] UVB-induced skin inflammation Promotion of inflammation after ET-1-mediated activation [68] Snake bites Degradation of toxic venom components [21]
  5. 5. 238 Review TRENDS in Immunology Vol.28 No.5 responses towards Th1. Indeed, skin MCs proved to be and, thus, reduce the overall morbidity and mortality crucial for the induction of normal systemic protection, [20]. thus indicating that MCs can help to control parasite Interestingly, the amino acid sequence of ET-1 exhibits infections both through innate mechanisms and through a remarkable similarity to that of sarafotoxin 6b (S6b) [50], their contribution to adaptive immune responses [39]. the most toxic component of the venom of the Israeli mole viper (Atractaspis engaddensis). This suggested a promi- Effector functions of mast cell-derived proteases nent role of MCs in a different innate response, namely The major MC proteases in the mouse are chymases enhancing the resistance of mice to A. engaddensis venom. (mMCP-1, mMCP-2, mMCP-4, mMCP-5 and mMCP-9), Indeed, MC-deficient mice were found to be 10-fold more tryptases [mMCP-6, mMCP-7, mMCP-11 and transmem- susceptible to the deadly effects of the venom than wild- brane tryptase (mTMT)] and carboxypeptidase A (mMC- type mice, and MC-derived carboxypeptidase A was proven CPA; Figure 2) [40,41]. Although recent reports were able to be responsible for enhancing the resistance against the to characterize some important effector functions for var- venomous effects [21]. MCs have long been thought to ious of these MC proteases, additional investigations are promote the pathology following snake bites, for example still needed to elucidate fully their in vivo functions and by releasing vasoactive mediators such as histamine, their substrates [60–62]. which can increase vascular permeability, facilitate both In addition to the above described function of mMCP-1 in local tissue swelling and the systemic distribution of the the expulsion of parasites [27,28], Tchougounova et al. have venom, and increase its overall toxicity [51,52]. The finding shown that mMCP-4, which most probably represents the that MCs instead elicit a protective innate response result- murine homolog of the human chymase [42], has a central ing in enhanced resistance to the venom of A. engaddensis role in the activation of matrix metalloprotease (MMP)-2 was, therefore, unexpected. Furthermore, MCs were found and MMP-9, which implies an important role for this chy- to protect, at least in part by releasing proteases, against mase in connective tissue homeostasis [43]. Furthermore, the venom from two species of pit vipers (Crotalinae) that tryptases might be involved in innate immune responses as produce venom that contains several different toxins mMCP-6 has been shown to induce long-lasting inflam- but not ET-1-like peptides. Additionally, MC-deficient mation with the associated accumulation of neutrophils mice are also far more susceptible than wild-type or MC- when injected intraperitoneally into mice [44], and human engrafted c-kit mutant mice to honeybee (Apis mellifera) tryptase b1, when administered into the trachea of venom-induced hypothermia, gross hematuria and death MC-deficient mice, protects against Klebsiella pneumoniae [21]. These observations extend our understanding of the infection of the lung [45]. Other possible mechanisms of how role of MCs in innate responses and will probably lead to tryptases might be involved in immune responses include the identification of other toxins that can be regulated by the expression of mouse transmembrane tryptase (mTMT) MCs. Whether similar mechanisms occur in humans is as on the surface of activated MCs. Human recombinant TMT yet unknown and difficult to predict from the available (which is 74% identical to mTMT) has been shown to mouse data. Human MCs, like mouse MCs, contain high increase the IL-13 production of T cells and mediate airway amounts of proteases including carboxypeptidase A, hyper-responsiveness in mice [46,47]. Because IL-13 is an one chymase and different tryptases, depending on the important Th2 cytokine, this interaction could also be microenvironment. Therefore, it is likely that human relevant in other immune responses. Additionally, MC MC-derived proteases also can enhance the resistance tryptases can activate protease-activated receptor (PAR)2, against toxic endogenous or exogenous peptides. which can lead to inflammation of the airways, joints and It will be of great interest to investigate whether the kidney [48], but might also contribute to host defense ability of MCs to be activated by venom-specific IgE anti- through the elicitation of a protective inflammatory reaction bodies bound to FceRI in sensitized animals or even (Figure 2). humans can actually enhance resistance against the toxicity of the venoms as compared with non-sensitized Enhancing resistance to endogenous and exogenous subjects. This hypothesis could provide an explanation for toxins the evolutionary development of a MC hypersensitivity to As mentioned earlier, there is recent evidence showing venom components which, although beneficial for the that MC-derived proteases promote homeostasis after host in general, can become inordinately extensive in bacterial infection through the limitation of ET-1-induced some individuals and can even result in life-threatening toxicity. ET-1 is thought to have a role in the pathogen- anaphylaxis. esis of various diseases; for example, levels of ET-1 in patients with sepsis correlate with the severity of the Mast cells initiate complex immune responses disease, and in murine models of sepsis or septic perito- In addition to the well-studied role of MCs in innate nitis, ET-1 contributes to the morbidity and mortality immune responses, there is increasing evidence that following infection [20,49]. The toxic effects of the pep- MCs can be important both in IgE-dependent (e.g. in tide, both after administration of exogenous ET-1 and in allergic responses and in responses to parasites) and the context of septic peritonitis, have been shown to be IgE-independent acquired immune responses, in which dramatically reduced by MCs. MCs are activated by ET-1 they can participate in the transition from the innate to through ET receptors expressed on the surface and sub- the adaptive phase of immune responses by interacting sequently release their mediators, including proteases, with other immune cells such as dendritic cells, B cells and that can then reduce the concentrations of the peptide T cells. MC-derived TNF has been described earlier in this
  6. 6. Review TRENDS in Immunology Vol.28 No.5 239 review as a crucial mediator in the initiation of adequate elicitation of optimal host responses to a variety of patho- innate immune responses to bacteria and parasites gens. Furthermore, the list of known mechanisms that can [34,38,53]. However, there is new evidence that TNF lead to the activation of MCs in these settings, although and other MC mediators can also contribute to the devel- most probably far from complete, is constantly growing, as is opment of acquired immune responses to pathogens. Using our understanding of the protective effector mechanisms of MC knock-in mice, McLachlan et al., for example, showed these cells. However, it is of great importance to note that that the recruitment of T cells to draining lymph nodes is most of what we presently know is based on murine data. substantially increased by MC-derived TNF and that TNF Although we think that it is crucial to investigate any released by MCs is largely responsible for lymph node biological response in an in vivo setting to prove its relevance hypertrophy during infection with Escherichia coli [54]. (and the MC knock-in model provides an excellent tool for Similarly, Jawdat and colleagues recently reported an MC research), one has to be careful in extrapolating from the important role for MC-derived TNF in the migration of murine to the human system. Whereas human MCs also Langerhans cells from the skin to the draining lymph express a huge amount of potent immunomodulatory nodes in response to bacterial peptidoglycan [55]. Addition- mediators and share many of the same mechanisms of ally, they provide data indicating a MC- and complement- activation, there are certain functional differences between dependent but TNF-independent effect of peptidoglycan on murine and human MCs [59]. For example, human and lymph node hypertrophy [55]. Whether the MC-dependent mouse skin MCs exhibit some differences in their production differences observed in these studies also result in signifi- of certain cytokines, proteases and other MC products, and cant differences in clinical outcome (e.g. morbidity and in the expression of receptors, and these discrepancies could mortality to bacterial infection), has yet to be determined. impact greatly on the role and relevance of MCs in innate Another intriguing question is to what extent MCs are immune responses in humans. able to limit, suppress or terminate immune responses. Although few studies have addressed the potential anti- inflammatory role of MCs in vivo, it is known that several References 1 Rivera, J. and Gilfillan, A.M. (2006) Molecular regulation of mast cell MC mediators, including TGF-b, IL-4, IL-10 and hista- activation. J. Allergy Clin. Immunol. 117, 1214–1225 mine, can have anti-inflammatory properties and/or can 2 Gilfillan, A.M. and Tkaczyk, C. (2006) Integrated signalling pathways negatively regulate biological responses, and MCs could for mast-cell activation. Nat. Rev. Immunol. 6, 218–230 therefore be involved in suppressing immune responses. 3 Grimbaldeston, M.A. et al. (2006) Effector and potential Using the MC knock-in mouse model, Depinay et al. immunoregulatory roles of mast cells in IgE-associated acquired immune responses. Curr. Opin. Immunol. 18, 751–760 recently demonstrated that the activation of MCs can 4 Gregory, G.D. and Brown, M.A. (2006) Mast cells in allergy and result in immunosuppression [56]. 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