Mast cells as protectors of health
Authors: Anne Dudeck, Martin Köberle, Oliver Goldmann, Nicole Meyer, Jan Dudeck, Stefanie Lemmens, Manfred Rohde, Nestor González Roldán, Kirsten Dietze-Schwonberg, Zane Orinska, Eva Medina, Sven Hendrix, Martin Metz, Ana Claudia Zenclussen, Esther von Stebut, Tilo Biedermann
Journal: Journal of Allergy and Clinical Immunology (2018)

Mast cells (MCs), which are well known for their effector functions in TH2-skewed allergic and also autoimmune inflammation, have become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs, such as the skin or gut. MCs can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T-cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focuses on the beneficial effects of MCs on tissue homeostasis and elimination of toxins or venoms. MCs can enhance pathogen clearance in many bacterial, viral, and parasitic infections, such as through Toll-like receptor 2–triggered degranulation, secretion of antimicrobial cathelicidins, neutrophil recruitment, or provision of extracellular DNA traps. The role of MCs in tumors is more ambiguous; however, encouraging new findings show they can change the tumor microenvironment toward antitumor immunity when adequately triggered. Uterine tissue remodeling by α-chymase (mast cell protease [MCP] 5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in central nervous system trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, proteases, such as carboxypeptidase A, released by FcεRI-activated MCs detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MCs will help improve these advantageous effects and hint at ways to cut down detrimental MC actions. Mast cells (MCs), which are well known for their effector functions in TH2-skewed allergic and also autoimmune inflammation, have become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs, such as the skin or gut. MCs can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T-cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focuses on the beneficial effects of MCs on tissue homeostasis and elimination of toxins or venoms. MCs can enhance pathogen clearance in many bacterial, viral, and parasitic infections, such as through Toll-like receptor 2–triggered degranulation, secretion of antimicrobial cathelicidins, neutrophil recruitment, or provision of extracellular DNA traps. The role of MCs in tumors is more ambiguous; however, encouraging new findings show they can change the tumor microenvironment toward antitumor immunity when adequately triggered. Uterine tissue remodeling by α-chymase (mast cell protease [MCP] 5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in central nervous system trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, proteases, such as carboxypeptidase A, released by FcεRI-activated MCs detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MCs will help improve these advantageous effects and hint at ways to cut down detrimental MC actions. Circulating mast cell (MC) precursors migrate to various tissues and mature into multifaceted effector cells essential for many immune and physiologic functions (Fig 1). As tissue-resident sentinel cells lining interfaces between the organs and the environment, MCs critically contribute to the first line of host defense against invading pathogens.1Abraham S.N. St John A.L. Mast cell-orchestrated immunity to pathogens.Nat Rev Immunol. 2010; 10: 440-452Crossref PubMed Scopus (545) Google Scholar, 2Piliponsky A.M. Romani L. The contribution of mast cells to bacterial and fungal infection immunity.Immunol Rev. 2018; 282: 188-197Crossref PubMed Scopus (18) Google Scholar MCs can recognize and respond to invading pathogens through a wide array of pattern recognition receptors, including Toll-like receptors (TLR), Fc, and complement receptors. They can also sense cell stress and tissue damage through a range of receptors, including cytokines, alarmins, and purinergic receptors.3Marshall J.S. Mast-cell responses to pathogens.Nat Rev Immunol. 2004; 4: 787-799Crossref PubMed Scopus (600) Google Scholar, 4Migalovich-Sheikhet H. Friedman S. Mankuta D. Levi-Schaffer F. Novel identified receptors on mast cells.Front Immunol. 2012; 3: 238Crossref PubMed Scopus (47) Google Scholar After activation by FcεRI or other stimuli and mediated by complex machinery, including CD63 and other tetraspanins,5Köberle M. Kaesler S. Kempf W. Wölbing F. Biedermann T. Tetraspanins in mast cells.Front Immunol. 2012; 3: 106Crossref PubMed Scopus (12) Google Scholar MCs undergo degranulation, releasing preformed mediators of secretory granules within only minutes, followed by release of a plethora of de novo–synthesized soluble mediators.3Marshall J.S. Mast-cell responses to pathogens.Nat Rev Immunol. 2004; 4: 787-799Crossref PubMed Scopus (600) Google Scholar Because of this immediate response, MCs can respond faster than other tissue-resident immune cells to invading pathogens and therefore in many cases initiate immune responses. MC functions have been studied in vivo by using different models of MC deficiency or by using in vitro systems of both human and murine MCs. However, the informative value of in vitro systems is limited because MCs act in concert, and lively exchange with other tissue-resident or immigrating cells and both MC numbers and responses are influenced by the cellular network. Many of the studies addressing the functional relevance of MCs in vivo have been performed with c-Kit mutant mice as models of MC deficiency. Because the KIT receptor is widely expressed on several subsets of progenitor cells, some findings might account rather for pleiotropic effects of the Kit mutation than for specific MC-driven effects. For example, studies regarding neutrophil recruitment and functions have to be carefully discussed because beyond MC deficiency, KitW-sh/W-sh (W-sh) mice, which bear the W-sash inversion mutation, display neutrophilia,6Nigrovic P.A. Gray D.H. Jones T. Hallgren J. Kuo F.C. Chaletzky B. et al.Genetic inversion in mast cell-deficient (Wsh) mice interrupts corin and manifests as hematopoietic and cardiac aberrancy.Am J Pathol. 2008; 173: 1693-1701Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar whereas KitW/W-v (W-v) mice carrying mutations in the white spotting locus are characterized by neutropenia.7Sayed B.A. Christy A.L. Walker M.E. Brown M.A. 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. 2010; 184: 6891-6900Crossref PubMed Scopus (107) Google Scholar In the last years, several groups have developed mouse models that are MC deficient but lack abnormalities related to Kit expression or function (reviewed by Reber et al8Reber L.L. Marichal T. Galli S.J. New models for analyzing mast cell functions in vivo.Trends Immunol. 2012; 33: 613-625Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Two strains in which the Cre recombinase is expressed under the MC-specific carboxypeptidase A3 (Cpa) promotor, the Cpa3Cre/+ or so-called Cre-Master mice9Feyerabend T.B. Weiser A. Tietz A. Stassen M. Harris N. Kopf M. et al.Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity.Immunity. 2011; 35: 832-844Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar and the Cpa3-Cre; Mcl-1fl/fl or so-called "Hello Kitty" mice,10Lilla J.N. Chen C.C. Mukai K. BenBarak M.J. Franco C.B. Kalesnikoff J. et al.Reduced mast cell and basophil numbers and function in Cpa3-Cre; Mcl-1fl/fl mice.Blood. 2011; 118: 6930-6938Crossref PubMed Scopus (117) Google Scholar are characterized by a constitutive deficiency of all MC subsets and a pronounced reduction in basophil numbers. The Mcpt5-Cre line allows for constitutive MC depletion when crossed to the R-DTAfl/fl line in which the diphtheria toxin A chain is produced in Cre-expressing cells.11Peschke K. Weitzmann A. Heger K. Behrendt R. Schubert N. Scholten J. et al.IkappaB kinase 2 is essential for IgE-induced mast cell de novo cytokine production but not for degranulation.Cell Rep. 2014; 8: 1300-1307Abstract Full Text Full Text PDF PubMed Google Scholar, 12Voehringer D. Liang H.E. Locksley R.M. Homeostasis and effector function of lymphopenia-induced "memory-like" T cells in constitutively T cell-depleted mice.J Immunol. 2008; 180: 4742-4753Crossref PubMed Scopus (108) Google Scholar When crossed to the inducible diphtheria toxin receptor (iDTR) line, in which the diphtheria toxin (DT) receptor is expressed by Cre-expressing cells, Mcpt5-Cre iDTR mice can be used for an induced or local MC depletion on DT injection.13Dudeck A. Dudeck J. Scholten J. Petzold A. Surianarayanan S. Kohler A. et al.Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens.Immunity. 2011; 34: 973-984Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar Of note, because of expression of the Cre recombinase under the promoter of mast cell protease (MCP) 5, only connective tissue–type mast cells (CTMCs) are depleted in Mcpt5-Cre R-DTA or iDTR mice, whereas mucosal MCs and basophil numbers are not reduced.11Peschke K. Weitzmann A. Heger K. Behrendt R. Schubert N. Scholten J. et al.IkappaB kinase 2 is essential for IgE-induced mast cell de novo cytokine production but not for degranulation.Cell Rep. 2014; 8: 1300-1307Abstract Full Text Full Text PDF PubMed Google Scholar, 13Dudeck A. Dudeck J. Scholten J. Petzold A. Surianarayanan S. Kohler A. et al.Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens.Immunity. 2011; 34: 973-984Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar Importantly, the Mcpt5-Cre mice allow for an MC-specific inactivation of certain genes of interest when crossed to the respective floxed line. A further possibility of inducible MC depletion is provided by "Mas-TRECK" mice in which the DT receptor is expressed under the control of an Il4 gene enhancer element.14Otsuka A. Kubo M. Honda T. Egawa G. Nakajima S. Tanizaki H. et al.Requirement of interaction between mast cells and skin dendritic cells to establish contact hypersensitivity.PLoS One. 2011; 6: e25538Crossref PubMed Scopus (90) Google Scholar Consequently, comparing previous findings obtained in Kit mutant mice with those obtained with Kit-independent mouse models of MC deficiency or gene inactivation will provide further mechanistic details of MC responses and functions. MCs release preformed mediators and can trigger vascular responses within only minutes after inflammatory insult, in particular vasodilatation and vessel permeabilization resulting in tissue edema.2Piliponsky A.M. Romani L. The contribution of mast cells to bacterial and fungal infection immunity.Immunol Rev. 2018; 282: 188-197Crossref PubMed Scopus (18) Google Scholar, 13Dudeck A. Dudeck J. Scholten J. Petzold A. Surianarayanan S. Kohler A. et al.Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens.Immunity. 2011; 34: 973-984Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 15Ashina K. Tsubosaka Y. Nakamura T. Omori K. Kobayashi K. Hori M. et al.Histamine induces vascular hyperpermeability by increasing blood flow and endothelial barrier disruption in vivo.PLoS One. 2015; 10: e0132367Crossref PubMed Scopus (41) Google Scholar, 16Kondeti V. Al-Azzam N. Duah E. Thodeti C.K. Boyce J.A. Paruchuri S. 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Hartmann K. et al.Mast cell and macrophage chemokines CXCL1/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation.Blood. 2013; 121: 4930-4937Crossref PubMed Scopus (267) Google Scholar However, the specific connection and communication between MCs and macrophages still remains elusive, despite their dense network in various tissues. Similar to effects on neutrophils, an effect of MCs on DC functionality has been demonstrated under various conditions, including bacterial infections, response to pathogen-derived factors, and sterile inflammation. In various models we have shown that on inflammatory challenge in the skin, MCs promote DC migration to skin-draining LNs and thereby critically support T cell–driven adaptive immune responses.13Dudeck A. Dudeck J. Scholten J. Petzold A. Surianarayanan S. 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Mast cell-orchestrated immunity to pathogens.Nat Rev Immunol. 2010; 10: 440-452Crossref PubMed Scopus (545) Google Scholar, 2Piliponsky A.M. Romani L. The contribution of mast cells to bacterial and fungal infection immunity.Immunol Rev. 2018; 282: 188-197Crossref PubMed Scopus (18) Google Scholar, 38Johnzon C.F. Ronnberg E. Pejler G. The role of mast cells in bacterial infection.Am J Pathol. 2016; 186: 4-14Abstract Full Text Full Text PDF PubMed Google Scholar Detection of invading bacteria is afforded by an array of receptors, including TLR, FimH receptor (CD48), and complement and Fc receptors. Sensing of bacterial products and humoral factors of the innate immune system results in MC degranulation, with concomitant release of a wide selection of biological active antimicrobial compounds and proinflammatory cytokines and chemokines.39Scheb-Wetzel M. Rohde M. Bravo A. Goldmann O. 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For example, it has been reported that MC-mediated release of TNF promotes neutrophil recruitment to the site of Klebsiella pneumonia infection,18Malaviya R. Ikeda T. Ross E. Abraham S.N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha.Nature. 1996; 381: 77-80Crossref PubMed Scopus (927) Google Scholar whereas secretion of cathelicidins by MCs has direct bactericidal effects on Streptococcus pyogenes.43Di Nardo A. Yamasaki K. Dorschner R.A. Lai Y. Gallo R.L. Mast cell cathelicidin antimicrobial peptide prevents invasive group A Streptococcus infection of the skin.J Immunol. 2008; 180: 7565-7573Crossref PubMed Google Scholar In this context it has been shown that MCs undergo degranulation on TLR2-mediated sensing of Staphylococcus aureus44Abel J. Goldmann O. Ziegler C. Holtje C. Smeltzer M.S. 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Hasegawa M. et al.Staphylococcus delta-toxin induces allergic skin disease by activating mast cells.Nature. 2013; 503: 397-401Crossref PubMed Scopus (208) Google Scholar MCs can also directly participate in bacterial killing through phagocytosis46Malaviya R. Ross E.A. MacGregor J.I. Ikeda T. Little J.R. Jakschik B.A. et al.Mast cell phagocytosis of FimH-expressing enterobacteria.J Immunol. 1994; 152: 1907-1914PubMed Google Scholar or release of extracellular traps (Fig 3, A) composed of DNA, histones, and MC-specific granule proteins, such as tryptase and cathelin-related antimicrobial peptide (CRAMP)/LL-37, where pathogens are captured and killed.39Scheb-Wetzel M. Rohde M. Bravo A. Goldmann O. New insights into the antimicrobial effect of mast cells against Enterococcus faecalis.Infect Immun. 2014; 82: 4496-4507Crossref PubMed Scopus (0) Google Scholar, 44Abel J. Goldmann O. Ziegler C. Holtje C. Smeltzer M.S. 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