Mast cell secretory granules are lysosome-like organelles that contain a large panel of preformed bioactive constituents, including lysosomal hydrolases, amines, cytokines, proteases and proteoglycans.
Mast cell granule biogenesis is initiated in the trans-Golgi and is followed by extensive maturation processes, which are strongly dependent on proteoglycans of the serglycin type.
When mast cells are activated — for example, in the context of an allergic reaction — degranulation occurs, whereby the bioactive granule compounds are expelled to the cell exterior and can cause a powerful inflammatory reaction.
Mast cell degranulation is a highly complex process that involves a large number of kinases, adaptor molecules and second messengers, as well as extensive membrane fusion events, which are mediated by numerous factors.
Mast cells are implicated in many pathological conditions and their effects in such settings are often mediated by the compounds that are secreted from the mast cell granules.
Recent research has indicated that the mast cell-specific proteases — chymases, tryptases and carboxypeptidase A3 — account for many of the functions that are ascribed to mast cells.
Mast cells are important effector cells of the immune system and recent studies show that they have immunomodulatory roles in diverse processes in both health and disease. Mast cells are distinguished by their high content of electron-dense secretory granules, which are filled with large amounts of preformed and pre-activated immunomodulatory compounds. When appropriately activated, mast cells undergo degranulation, a process by which these preformed granule compounds are rapidly released into the surroundings. In many cases, the effects that mast cells have on an immune response are closely associated with the biological actions of the granule compounds that they release, as exemplified by the recent studies showing that mast cell granule proteases account for many of the protective and detrimental effects of mast cells in various inflammatory settings. In this Review, we discuss the current knowledge of mast cell secretory granules.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
IL-33-mediated activation of mast cells is involved in the progression of imiquimod-induced psoriasis-like dermatitis
Cell Communication and Signaling Open Access 09 March 2023
The molecular mechanisms of remodeling in asthma, COPD and IPF with a special emphasis on the complex role of Wnt5A
Inflammation Research Open Access 19 January 2023
Role of GRPR in Acupuncture Intervention in the “Itch-scratch Vicious Cycle” Spinal Circuit of Chronic Pruritus
Chinese Medicine Open Access 03 January 2023
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Metcalfe, D. D., Baram, D. & Mekori, Y. A. Mast cells. Physiol. Rev. 77, 1033–1079 (1997).
Gurish, M. F. & Austen, K. F. Developmental origin and functional specialization of mast cell subsets. Immunity 37, 25–33 (2012).
Galli, S. J., Nakae, S. & Tsai, M. Mast cells in the development of adaptive immune responses. Nature Immunol. 6, 135–142 (2005).
Marshall, J. S. Mast-cell responses to pathogens. Nature Rev. Immunol. 4, 787–799 (2004).
St John, A. L. & Abraham, S. N. Innate immunity and its regulation by mast cells. J. Immunol. 190, 4458–4463 (2013).
Galli, S. J. et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749–786 (2005).
Feyerabend, T. B. et al. Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity. Immunity 35, 832–844 (2011).
Dudeck, A. et al. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 34, 973–984 (2011).
Rodewald, H. R. & Feyerabend, T. B. Widespread immunological functions of mast cells: fact or fiction? Immunity 37, 13–24 (2012).
Reber, L. L., Marichal, T. & Galli, S. J. New models for analyzing mast cell functions in vivo. Trends Immunol. 33, 613–625 (2012).
Arvan, P. & Castle, D. Sorting and storage during secretory granule biogenesis: looking backward and looking forward. Biochem. J. 332, 593–610 (1998).
Blott, E. J. & Griffiths, G. M. Secretory lysosomes. Nature Rev. Mol. Cell Biol. 3, 122–131 (2002).
Pejler, G., Åbrink, M., Ringvall, M. & Wernersson, S. Mast cell proteases. Adv. Immunol. 95, 167–255 (2007).
Rönnberg, E., Melo, F. R. & Pejler, G. Mast cell proteoglycans. J. Histochem. Cytochem. 60, 950–962 (2012).
Puri, N. & Roche, P. A. Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms. Proc. Natl Acad. Sci. USA 105, 2580–2585 (2008).
Theoharides, T. C., Bondy, P. K., Tsakalos, N. D. & Askenase, P. W. Differential release of serotonin and histamine from mast cells. Nature 297, 229–231 (1982).
Kanerva, K. et al. Expression of antizyme inhibitor 2 in mast cells and role of polyamines as selective regulators of serotonin secretion. PLoS ONE 4, e6858 (2009).
Baram, D. et al. Synaptotagmin II negatively regulates Ca2+-triggered exocytosis of lysosomes in mast cells. J. Exp. Med. 189, 1649–1658 (1999).
Dvorak, A. M. Ultrastructural studies of human basophils and mast cells. J. Histochem. Cytochem. 53, 1043–1070 (2005).
Whitaker-Menezes, D., Schechter, N. M. & Murphy, G. F. Serine proteinases are regionally segregated within mast cell granules. Lab Invest. 72, 34–41 (1995).
Hammel, I. et al. Differences in the volume distributions of human lung mast cell granules and lipid bodies: evidence that the size of these organelles is regulated by distinct mechanisms. J. Cell Biol. 100, 1488–1492 (1985).
Combs, J. W. Maturation of rat mast cells. An electron microscope study. J. Cell Biol. 31, 563–575 (1966).
Hammel, I., Lagunoff, D. & Galli, S. J. Regulation of secretory granule size by the precise generation and fusion of unit granules. J. Cell. Mol. Med. 14, 1904–1916 (2010).
Prasad, P., Yanagihara, A. A., Small-Howard, A. L., Turner, H. & Stokes, A. J. Secretogranin III directs secretory vesicle biogenesis in mast cells in a manner dependent upon interaction with chromogranin A. J. Immunol. 181, 5024–5034 (2008).
Azouz, N. P. et al. Rab5 is a novel regulator of mast cell secretory granules: impact on size, cargo, and exocytosis. J. Immunol. 192, 4043–4053 (2014).
Dvorak, A. M., Hammel, I. & Galli, S. J. Beige mouse mast cells generated in vitro: ultrastructural analysis of maturation induced by sodium butyrate and of IgE-mediated, antigen-dependent degranulation. Int. Arch. Allergy Appl. Immunol. 82, 261–268 (1987).
Hammel, I., Dvorak, A. M. & Galli, S. J. Defective cytoplasmic granule formation. I. Abnormalities affecting tissue mast cells and pancreatic acinar cells of beige mice. Lab Invest. 56, 321–328 (1987).
Grimberg, E., Peng, Z., Hammel, I. & Sagi-Eisenberg, R. Synaptotagmin III is a critical factor for the formation of the perinuclear endocytic recycling compartment and determination of secretory granules size. J. Cell Sci. 116, 145–154 (2003).
Olszewski, M. B., Trzaska, D., Knol, E. F., Adamczewska, V. & Dastych, J. Efficient sorting of TNF-alpha to rodent mast cell granules is dependent on N-linked glycosylation. Eur. J. Immunol. 36, 997–1008 (2006).
Henningsson, F., Hergeth, S., Cortelius, R., Åbrink, M. & Pejler, G. A role for serglycin proteoglycan in granular retention and processing of mast cell secretory granule components. FEBS J. 273, 4901–4912 (2006).
Haberman, Y. et al. Synaptotagmin (Syt) IX is an essential determinant for protein sorting to secretory granules in mast cells. Blood 109, 3385–3392 (2007).
Merickel, A. & Edwards, R. H. Transport of histamine by vesicular monoamine transporter-2. Neuropharmacology 34, 1543–1547 (1995).
Kruger, P. G. & Lagunoff, D. Effect of age on mast cell granules. Int. Arch. Allergy Appl. Immunol. 65, 291–299 (1981).
Hammel, I., Lagunoff, D. & Kruger, P. G. Studies on the growth of mast cells in rats. Changes in granule size between 1 and 6 months. Lab Invest. 59, 549–554 (1988).
Hammel, I., Lagunoff, D. & Kruger, P. G. Recovery of rat mast cells after secretion: a morphometric study. Exp. Cell Res. 184, 518–523 (1989).
Kruger, P. G. & Lagunoff, D. Mast cell restoration. A study of the rat peritoneal mast cells after depletion with polymyxin B. Int. Arch. Allergy Appl. Immunol. 65, 278–290 (1981).
Ringvall, M. et al. Serotonin and histamine storage in mast cell secretory granules is dependent on serglycin proteoglycan. J. Allergy Clin. Immunol. 121, 1020–1026 (2008).
Gurish, M. F. et al. Differential expression of secretory granule proteases in mouse mast cells exposed to interleukin 3 and c-kit ligand. J. Exp. Med. 175, 1003–1012 (1992).
Duelli, A. et al. Mast cell differentiation and activation is closely linked to expression of genes coding for the serglycin proteoglycan core protein and a distinct set of chondroitin sulfate and heparin sulfotransferases. J. Immunol. 183, 7073–7083 (2009).
Butterfield, J. H., Weiler, D., Peterson, E. A., Gleich, G. J. & Leiferman, K. M. Sequestration of eosinophil major basic protein in human mast cells. Lab Invest. 62, 77–86 (1990).
Ohtsu, H. et al. Plasma extravasation induced by dietary supplemented histamine in histamine-free mice. Eur. J. Immunol. 32, 1698–1708 (2002).
Rundquist, I., Allenmark, S. & Enerbäck, L. Uptake and turnover of dopamine in rat mast cells studied by cytofluorometry and high performance liquid chromatography. Histochem. J. 14, 429–443 (1982).
Rickard, A. & Lagunoff, D. Eosinophil peroxidase accounts for most if not all of the peroxidase activity associated with isolated rat peritoneal mast cells. Int. Arch. Allergy Immunol. 103, 365–369 (1994).
Olszewski, M. B., Groot, A. J., Dastych, J. & Knol, E. F. TNF trafficking to human mast cell granules: mature chain-dependent endocytosis. J. Immunol. 178, 5701–5709 (2007).
Braga, T. et al. Serglycin proteoglycan is required for secretory granule integrity in mucosal mast cells. Biochem. J. 403, 49–57 (2007).
Åbrink, M., Grujic, M. & Pejler, G. Serglycin is essential for maturation of mast cell secretory granule. J. Biol. Chem. 279, 40897–40905 (2004).
Forsberg, E. et al. Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme. Nature 400, 773–776 (1999).
Humphries, D. E. et al. Heparin is essential for the storage of specific granule proteases in mast cells. Nature 400, 769–772 (1999). References 47 and 48 show for the first time that proteoglycans are crucial for promoting the storage of diverse compounds (in particular, proteases) in mast cell granules.
Wang, B. et al. Heparanase affects secretory granule homeostasis of murine mast cells through degrading heparin. J. Allergy Clin. Immunol. 128, 1310–1317 (2011).
Ohtake-Niimi, S. et al. Mice deficient in N-acetylgalactosamine 4-sulfate 6-o-sulfotransferase are unable to synthesize chondroitin/dermatan sulfate containing N-acetylgalactosamine 4,6-bissulfate residues and exhibit decreased protease activity in bone marrow-derived mast cells. J. Biol. Chem. 285, 20793–20805 (2010).
Skokos, D. et al. Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes. J. Immunol. 166, 868–876 (2001).
Ohtsu, H. et al. Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett. 502, 53–56 (2001).
Nakazawa, S. et al. Histamine synthesis is required for granule maturation in murine mast cells. Eur. J. Immunol. 44, 204–214 (2013).
Csaba, G., Kovacs, P., Buzas, E., Mazan, M. & Pallinger, E. Serotonin content is elevated in the immune cells of histidine decarboxylase gene knock-out (HDCKO) mice. Focus on mast cells. Inflamm. Res. 56, 89–92 (2007).
Garcia-Faroldi, G. et al. Polyamines are present in mast cell secretory granules and are important for granule homeostasis. PLoS ONE 5, e15071 (2010).
Grujic, M. et al. Distorted secretory granule composition in mast cells with multiple protease deficiency. J. Immunol. 191, 3931–3938 (2013).
Feyerabend, T. B. et al. Loss of histochemical identity in mast cells lacking carboxypeptidase A. Mol. Cell. Biol. 25, 6199–6210 (2005).
Younan, G. et al. The inflammatory response after an epidermal burn depends on the activities of mouse mast cell proteases 4 and 5. J. Immunol. 185, 7681–7690 (2010).
Stevens, R. L. et al. Transgenic mice that possess a disrupted mast cell protease 5 (mMCP-5) gene can not store carboxypeptidase A (mMC-CPA) protein in their granules. FASEB J. 10, 17772 (1996).
Wolters, P. J., Pham, C. T., Muilenburg, D. J., Ley, T. J. & Caughey, G. H. Dipeptidyl peptidase I is essential for activation of mast cell chymases, but not tryptases, in mice. J. Biol. Chem. 276, 18551–18556 (2001).
Henningsson, F. et al. A role for cathepsin E in the processing of mast-cell carboxypeptidase A. J. Cell Sci. 118, 2035–2042 (2005).
Springman, E. B., Dikov, M. M. & Serafin, W. E. Mast cell procarboxypeptidase A. Molecular modeling and biochemical characterization of its processing within secretory granules. J. Biol. Chem. 270, 1300–1307 (1995).
Le, Q. T. et al. Processing of human protryptase in mast cells involves cathepsins L, B, and C. J. Immunol. 187, 1912–1918 (2011).
Rath-Wolfson, L. An immunocytochemical approach to the demonstration of intracellular processing of mast cell carboxypeptidase. Appl. Immunohistochem. Mol. Morphol. 9, 81–85 (2001).
Rivera, J., Fierro, N. A., Olivera, A. & Suzuki, R. New insights on mast cell activation via the high affinity receptor for IgE. Adv. Immunol. 98, 85–120 (2008).
Kraft, S. & Kinet, J. P. New developments in FcɛRI regulation, function and inhibition. Nature Rev. Immunol. 7, 365–378 (2007).
Lorentz, A., Baumann, A., Vitte, J. & Blank, U. The SNARE machinery in mast cell secretion. Front. Immunol. 3, 143 (2012).
Tiwari, N. et al. VAMP-8 segregates mast cell-preformed mediator exocytosis from cytokine trafficking pathways. Blood 111, 3665–3674 (2008). This elegant study identifies a crucial role for VAMP8 in mast cell degranulation.
Sander, L. E. et al. Vesicle associated membrane protein (VAMP)-7 and VAMP-8, but not VAMP-2 or VAMP-3, are required for activation-induced degranulation of mature human mast cells. Eur. J. Immunol. 38, 855–863 (2008).
Brochetta, C. et al. Munc18-2 and syntaxin 3 control distinct essential steps in mast cell degranulation. J. Immunol. 192, 41–51 (2014).
Paumet, F. et al. Soluble NSF attachment protein receptors (SNAREs) in RBL-2H3 mast cells: functional role of syntaxin 4 in exocytosis and identification of a vesicle-associated membrane protein 8-containing secretory compartment. J. Immunol. 164, 5850–5857 (2000).
Guo, Z., Turner, C. & Castle, D. Relocation of the t-SNARE SNAP-23 from lamellipodia-like cell surface projections regulates compound exocytosis in mast cells. Cell 94, 537–548 (1998).
Tadokoro, S., Nakanishi, M. & Hirashima, N. Complexin II facilitates exocytotic release in mast cells by enhancing Ca2+ sensitivity of the fusion process. J. Cell Sci. 118, 2239–2246 (2005).
Mizuno, K. et al. Rab27b regulates mast cell granule dynamics and secretion. Traffic 8, 883–892 (2007).
Melicoff, E. et al. Synaptotagmin-2 controls regulated exocytosis but not other secretory responses of mast cells. J. Biol. Chem. 284, 19445–19451 (2009).
Kraft, S. et al. The tetraspanin CD63 is required for efficient IgE-mediated mast cell degranulation and anaphylaxis. J. Immunol. 191, 2871–2878 (2013).
Neeft, M. et al. Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. Mol. Biol. Cell 16, 731–741 (2005).
Nishida, K. et al. FcɛRI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane. J. Cell Biol. 170, 115–126 (2005).
Deng, Z. et al. Impact of actin rearrangement and degranulation on the membrane structure of primary mast cells: a combined atomic force and laser scanning confocal microscopy investigation. Biophys. J. 96, 1629–1639 (2009).
Foger, N. et al. Differential regulation of mast cell degranulation versus cytokine secretion by the actin regulatory proteins Coronin1a and Coronin1b. J. Exp. Med. 208, 1777–1787 (2011).
Dvorak, A. M. Piecemeal degranulation of basophils and mast cells is effected by vesicular transport of stored secretory granule contents. Chem. Immunol. Allergy 85, 135–184 (2005).
Palm, N. W., Rosenstein, R. K. & Medzhitov, R. Allergic host defences. Nature 484, 465–472 (2012).
Wastling, J. M. et al. Histochemical and ultrastructural modification of mucosal mast cell granules in parasitized mice lacking the β-chymase, mouse mast cell protease-1. Am. J. Pathol. 153, 491–504 (1998). This is the first study to report a knockout of a mast cell-specific granule compound.
Tchougounova, E., Pejler, G. & Åbrink, M. The chymase, mouse mast cell protease 4, constitutes the major chymotrypsin-like activity in peritoneum and ear tissue. A role for mouse mast cell protease 4 in thrombin regulation and fibronectin turnover. J. Exp. Med. 198, 423–431 (2003).
Shin, K. et al. 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 (2008).
Thakurdas, S. M. et al. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections. J. Biol. Chem. 282, 20809–20815 (2007). This is the first study to prove a role for a mast cell granule-specific compound in antibacterial defence.
Scholten, J. et al. Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgen. Res. 17, 307–315 (2008).
Ohtsu, H. Pathophysiologic role of histamine: evidence clarified by histidine decarboxylase gene knockout mice. Int. Arch. Allergy Immunol. 158 (Suppl. 1), 2–6 (2012).
Molinari, J. F. et al. Inhaled tryptase causes bronchoconstriction in sheep via histamine release. Am. J. Respir. Crit. Care Med. 154, 649–653 (1996).
He, S. & Walls, A. F. Human mast cell chymase induces the accumulation of neutrophils, eosinophils and other inflammatory cells in vivo. Br. J. Pharmacol. 125, 1491–1500 (1998).
Huang, C. et al. Induction of a selective and persistent extravasation of neutrophils into the peritoneal cavity by tryptase mouse mast cell protease 6. J. Immunol. 160, 1910–1919 (1998). References 89–91 establish that purified mast cell granule proteases are pro-inflammatory.
Clark, J. M. et al. Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep. Am. J. Respir. Crit. Care Med. 152, 2076–2083 (1995).
Watanabe, N., Miura, K. & Fukuda, Y. Chymase inhibitor ameliorates eosinophilia in mice infected with Nippostrongylus brasiliensis. Int. Arch. Allergy Immunol. 128, 235–239 (2002).
Bankova, L. G. et al. Mouse mast cell proteases 4 and 5 mediate epidermal injury through disruption of tight junctions. J Immunol. 192, 2812–2820 (2014).
Sun, J. et al. Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation. Circulation 120, 973–982 (2009).
Reber, L. L., Daubeuf, F., Pejler, G., Abrink, M. & Frossard, N. Mast cells contribute to bleomycin-induced lung inflammation and injury in mice through a chymase/mast cell protease 4-dependent mechanism. J. Immunol. 192, 1847–1854 (2014).
Hamilton, M. J. et al. Essential role for mast cell tryptase in acute experimental colitis. Proc. Natl Acad. Sci. USA 108, 290–295 (2011).
Hellman, L. & Thorpe, M. Granule proteases of hematopoietic cells, a family of versatile inflammatory mediators — an update on their cleavage specificity, in vivo substrates, and evolution. Biol. Chem. 395, 15–49 (2014).
Mirza, H., Schmidt, V. A., Derian, C. K., Jesty, J. & Bahou, W. F. Mitogenic responses mediated through the proteinase-activated receptor-2 are induced by expressed forms of mast cell alpha- or beta-tryptases. Blood 90, 3914–3922 (1997).
Molino, M. et al. Interactions of mast cell tryptase with thrombin receptors and PAR-2. J. Biol. Chem. 272, 4043–4049 (1997).
Prieto-Garcia, A. et al. Mast cell restricted mouse and human tryptase.heparin complexes hinder thrombin-induced coagulation of plasma and the generation of fibrin by proteolytically destroying fibrinogen. J. Biol. Chem. 287, 7834–7844 (2012).
McDermott, J. R. et al. Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc. Natl Acad. Sci. USA 100, 7761–7766 (2003). This study provides mechanistic insight into the protective role of mast cells during parasite infection by showing that mast cell proteases can promote epithelial permeability by degrading tight junction proteins.
Groschwitz, K. R., Wu, D., Osterfeld, H., Ahrens, R. & Hogan, S. P. Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor/matrix metalloproteinase-2-dependent mechanism. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G479–489 (2013).
Lin, L. et al. Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid. J. Biol. Chem. 286, 37358–37367 (2011).
Urata, H., Kinoshita, A., Misono, K. S., Bumpus, F. M. & Husain, A. Identification of a highly specific chymase as the major angiotensin II- forming enzyme in the human heart. J. Biol. Chem. 265, 22348–22357 (1990).
Houde, M. et al. Pivotal role of mouse mast cell protease 4 in the conversion and pressor properties of big-endothelin-1. J. Pharmacol. Exp. Ther. 346, 31–37 (2013).
Mizutani, H., Schechter, N., Lazarus, G., Black, R. A. & Kupper, T. S. Rapid and specific conversion of precursor interleukin 1β (IL-1β) to an active IL-1 species by human mast cell chymase. J. Exp. Med. 174, 821–825 (1991).
Omoto, Y. et al. Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment. J. Immunol. 177, 8315–8319 (2006).
Schiemann, F. et al. Mast cells and neutrophils proteolytically activate chemokine precursor CTAP-III and are subject to counterregulation by PF-4 through inhibition of chymase and cathepsin G. Blood 107, 2234–2242 (2006).
Berahovich, R. D. et al. Proteolytic activation of alternative CCR1 ligands in inflammation. J. Immunol. 174, 7341–7351 (2005).
Oschatz, C. et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity 34, 258–268 (2011).
Lagunoff, D. & Rickard, A. Mast cell granule heparin proteoglycan induces lacunae in confluent endothelial cell monolayers. Am. J. Pathol. 154, 1591–1600 (1999).
Waern, I. et al. Mouse mast cell protease 4 is the major chymase in murine airways and has a protective role in allergic airway inflammation. J. Immunol. 183, 6369–6376 (2009).
Waern, I., Lundequist, A., Pejler, G. & Wernersson, S. Mast cell chymase modulates IL-33 levels and controls allergic sensitization in dust-mite induced airway inflammation. Mucosal Immunol. 6, 911–920 (2013).
Yu, M. et al. Mast cells can promote the development of multiple features of chronic asthma in mice. J. Clin. Invest. 116, 1633–1641 (2006).
Williams, C. M. & Galli, S. J. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J. Exp. Med. 192, 455–462 (2000).
Nakae, S. et al. Mast cell-derived TNF contributes to airway hyperreactivity, inflammation, and TH2 cytokine production in an asthma model in mice. J. Allergy Clin. Immunol. 120, 48–55 (2007).
Hendrix, S. et al. Mast cells protect from post-traumatic brain inflammation by the mast cell-specific chymase mouse mast cell protease-4. FASEB J. 27, 920–929 (2013).
Nelissen, S. et al. Mast cells protect from post-traumatic spinal cord damage in mice by degrading inflammation-associated cytokines via mouse mast cell protease 4. Neurobiol Dis 62, 260–272 (2013).
Zhao, W., Oskeritzian, C. A., Pozez, A. L. & Schwartz, L. B. Cytokine production by skin-derived mast cells: endogenous proteases are responsible for degradation of cytokines. J. Immunol. 175, 2635–2642 (2005).
Waern, I. et al. Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis. Biol. Chem. 393, 1555–1567 (2012).
Roy, A. et al. Mast cell chymase degrades the alarmins heat shock protein 70, biglycan, HMGB1, and interleukin-33 (IL-33) and limits danger-induced inflammation. J. Biol. Chem. 289, 237–250 (2014).
Maurer, M. et al. Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 432, 512–516 (2004).
Metz, M. et al. Mast cells can enhance resistance to snake and honeybee venoms. Science 313, 526–530 (2006). This is a hallmark study identifying an essential role for CPA3 — a mast cell granule compound — in host defence against toxins.
Akahoshi, M. et al. Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice. J. Clin. Invest. 121, 4180–4191 (2011).
Schneider, L. A., Schlenner, S. M., Feyerabend, T. B., Wunderlin, M. & Rodewald, H. R. Molecular mechanism of mast cell mediated innate defense against endothelin and snake venom sarafotoxin. J. Exp. Med. 204, 2629–2639 (2007). In this study, the authors confirm by using an elegant approach that CPA3 is essential for protection against snake toxins and endothelin 1.
Malaviya, R., Ikeda, T., Ross, E. & Abraham, S. N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNFα. Nature 381, 77–80 (1996).
Echtenacher, B., Mannel, D. N. & Hultner, L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381, 75–77 (1996).
Piliponsky, A. M. et al. The chymase mouse mast cell protease 4 degrades TNF, limits inflammation, and promotes survival in a model of sepsis. Am. J. Pathol. 181, 875–886 (2012).
Orinska, Z. et al. IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. Nature Med. 13, 927–934 (2007).
Niemann, C. U. et al. Neutrophil elastase depends on serglycin proteoglycan for localization in granules. Blood 109, 4478–4486 (2007).
Hori, Y. et al. Accelerated clearance of Escherichia coli in experimental peritonitis of histamine-deficient mice. J. Immunol. 169, 1978–1983 (2002).
Knight, P. A., Wright, S. H., Lawrence, C. E., Paterson, Y. Y. & Miller, H. R. Delayed expulsion of the nematode Trichinella spiralis in mice lacking the mucosal mast cell-specific granule chymase, mouse mast cell protease-1. J. Exp. Med. 192, 1849–1856 (2000).
Chen, R. et al. Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J. Clin. Invest. 108, 1151–1158 (2001).
Lee, D. M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002).
Secor, V. H., Secor, W. E., Gutekunst, C. A. & Brown, M. A. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191, 813–822 (2000).
Magnusson, S. E., Pejler, G., Kleinau, S. & Abrink, M. Mast cell chymase contributes to the antibody response and the severity of autoimmune arthritis. FASEB J. 23, 875–882 (2009).
McNeil, H. P. et al. The mouse mast cell-restricted tetramer-forming tryptases mouse mast cell protease 6 and mouse mast cell protease 7 are critical mediators in inflammatory arthritis. Arthritis Rheum. 58, 2338–2346 (2008).
Shin, K. et al. Mast cells contribute to autoimmune inflammatory arthritis via their tryptase/heparin complexes. J. Immunol. 182, 647–656 (2009).
Rajasekaran, N. et al. Histidine decarboxylase but not histamine receptor 1 or 2 deficiency protects from K/BxN serum-induced arthritis. Int. Immunol. 21, 1263–1268 (2009).
Saarinen, J., Kalkkinen, N., Welgus, H. G. & Kovanen, P. T. Activation of human interstitial procollagenase through direct cleavage of the Leu83–Thr84 bond by mast cell chymase. J. Biol. Chem. 269, 18134–18140 (1994).
Fang, K. C., Raymond, W. W., Lazarus, S. C. & Caughey, G. H. Dog mastocytoma cells secrete a 92-kD gelatinase activated extracellularly by mast cell chymase. J. Clin. Invest. 97, 1589–1596 (1996).
Tchougounova, E. et al. A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J. Biol. Chem. 280, 9291–9296 (2005).
Magarinos, N. J. et al. Mast cell-restricted, tetramer-forming tryptases induce aggrecanolysis in articular cartilage by activating matrix metalloproteinase-3 and -13 zymogens. J. Immunol. 191, 1404–1412 (2013).
Beghdadi, W. et al. Mast cell chymase protects against renal fibrosis in murine unilateral ureteral obstruction. Kidney Int. 84, 317–326 (2013).
Fajardo, I. & Pejler, G. Human mast cell β-tryptase is a gelatinase. J. Immunol. 171, 1493–1499 (2003).
Scandiuzzi, L. et al. Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis. J. Immunol. 185, 624–633 (2010).
Algermissen, B., Hermes, B., Feldmann-Boeddeker, I., Bauer, F. & Henz, B. M. Mast cell chymase and tryptase during tissue turnover: analysis on in vitro mitogenesis of fibroblasts and keratinocytes and alterations in cutaneous scars. Exp. Dermatol. 8, 193–198 (1999).
Masubuchi, S. et al. Chymase inhibitor ameliorates hepatic steatosis and fibrosis on established non-alcoholic steatohepatitis in hamsters fed a methionine- and choline-deficient diet. Hepatol Res. 43, 970–978 (2013).
Kunder, C. A. et al. Mast cell-derived particles deliver peripheral signals to remote lymph nodes. J. Exp. Med. 206, 2455–2467 (2009). This study introduces the concept of granules acting as entities, mediating the transport of bioactive compounds from tissue mast cells to lymph nodes.
St John, A. L., Chan, C. Y., Staats, H. F., Leong, K. W. & Abraham, S. N. Synthetic mast-cell granules as adjuvants to promote and polarize immunity in lymph nodes. Nature Mater. 11, 250–257 (2012).
Wilhelm, M., Silver, R. & Silverman, A. J. Central nervous system neurons acquire mast cell products via transgranulation. Eur. J. Neurosci. 22, 2238–2248 (2005).
Dougherty, R.H. et al. Accumulation of intraepithelial mast cells with a unique protease phenotype in TH2-high asthma. J. Allergy Clin. Immunol. 125, 1046–1053 (2010).
Lundequist, A. & Pejler, G. Biological implications of preformed mast cell mediators. Cell. Mol. Life Sci. 68, 965–975 (2011).
Schwartz, L. B. & Austen, K. F. Enzymes of the mast cell granule. J. Invest. Dermatol. 74, 349–353 (1980).
Schwartz, L. B., Lewis, R. A., Seldin, D. & Austen, K. F. Acid hydrolases and tryptase from secretory granules of dispersed human lung mast cells. J. Immunol. 126, 1290–1294 (1981).
Schwartz, L. B., Austen, K. F. & Wasserman, S. I. Immunologic release of β-hexosaminidase and β-glucuronidase from purified rat serosal mast cells. J. Immunol. 123, 1445–1450 (1979).
Dragonetti, A. et al. The lysosomal protease cathepsin D is efficiently sorted to and secreted from regulated secretory compartments in the rat basophilic/mast cell line RBL. J. Cell Sci. 113, 3289–3298 (2000).
Wolters, P. J., Laig-Webster, M. & Caughey, G. H. Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed mainly by mast cells in normal dog airways. Am. J. Respir. Cell. Mol. Biol. 22, 183–190 (2000).
Riley, J. F. Histamine in tissue mast cells. Science 118, 332 (1953).
Sjoerdsma, A., Waalkes, T. P. & Weissbach, H. Serotonin and histamine in mast cells. Science 125, 1202–1203 (1957).
Benditt, E. P., Wong, R. L., Arase, M. & Roeper, E. 5-Hydroxytryptamine in mast cells. Proc. Soc. Exp. Biol. Med. 90, 303–304 (1955).
Kushnir-Sukhov, N. M., Brown, J. M., Wu, Y., Kirshenbaum, A. & Metcalfe, D. D. Human mast cells are capable of serotonin synthesis and release. J. Allergy Clin. Immunol. 119, 498–499 (2007).
Freeman, J. G. et al. Catecholamines in murine bone marrow derived mast cells. J. Neuroimmunol. 119, 231–238 (2001).
Gordon, J. R. & Galli, S. J. Mast cells as a source of both preformed and immunologically inducible TNFα/cachectin. Nature 346, 274–276 (1990). This is the first study in which mast cell granules were shown to contain preformed stored cytokines.
Bradding, P. et al. Interleukin 4 is localized to and released by human mast cells. J. Exp. Med. 176, 1381–1386 (1992).
Reed, J. A., Albino, A. P. & McNutt, N. S. Human cutaneous mast cells express basic fibroblast growth factor. Lab Invest. 72, 215–222 (1995).
Grutzkau, A. et al. 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 (1998).
Boesiger, J. et al. Mast cells can secrete vascular permeability factor/ vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of Fcɛ receptor I expression. J. Exp. Med. 188, 1135–1145 (1998).
Lindstedt, K. A. et al. Activation of paracrine TGF-β1 signaling upon stimulation and degranulation of rat serosal mast cells: a novel function for chymase. FASEB J. 15, 1377–1388 (2001).
Leon, A. et al. Mast cells synthesize, store, and release nerve growth factor. Proc. Natl Acad. Sci. USA 91, 3739–3743 (1994).
Bradding, P. et al. Immunolocalization 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 (1993).
Zhang, S. et al. Human mast cells express stem cell factor. J. Pathol. 186, 59–66 (1998).
Glenner, G. G. & Cohen, L. A. Histochemical demonstration of a species-specific trypsin-like enzyme in mast cells. Nature 185, 846–847 (1960).
Benditt, E. P. & Arase, M. An enzyme in mast cells with properties like chymotrypsin. J. Exp. Med. 110, 451–460 (1959).
Haas, R., Heinrich, P. C. & Sasse, D. Proteolytic enzymes of rat liver mitochondria. Evidence for a mast cell origin. FEBS Lett. 103, 168–171 (1979).
Schechter, N. M. et al. Identification of a cathepsin G-like proteinase in the MCTC type of human mast cell. J. Immunol. 145, 2652–2661 (1990).
Baram, D. et al. Human mast cells release metalloproteinase-9 on contact with activated T cells: juxtacrine regulation by TNF-α. J. Immunol. 167, 4008–4016 (2001).
Garcia-Faroldi, G., Melo, F. R., Ronnberg, E., Grujic, M. & Pejler, G. Active caspase-3 is stored within secretory compartments of viable mast cells. J. Immunol. 191, 1445–1452 (2013).
Zorn, C. N. et al. Secretory lysosomes of mouse mast cells store and exocytose active caspase-3 in a strictly granzyme B dependent manner. Eur. J. Immunol. 43, 3209–3218 (2013).
Garcia-Faroldi, G. et al. ADAMTS: novel proteases expressed by activated mast cells. Biol. Chem. 394, 291–305 (2013).
Pardo, J. et al. Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin. Cell Death Differ. 14, 1768–1779 (2007).
Silver, R. B. et al. Mast cells: a unique source of renin. Proc. Natl Acad. Sci. USA 101, 13607–13612 (2004).
Frank, S. P., Thon, K. P., Bischoff, S. C. & Lorentz, A. SNAP-23 and syntaxin-3 are required for chemokine release by mature human mast cells. Mol. Immunol. 49, 353–358 (2011).
Hibi, T., Hirashima, N. & Nakanishi, M. Rat basophilic leukemia cells express syntaxin-3 and VAMP-7 in granule membranes. Biochem. Biophys. Res. Commun. 271, 36–41 (2000).
Martin-Verdeaux, S. et al. Evidence of a role for Munc18-2 and microtubules in mast cell granule exocytosis. J. Cell Sci. 116, 325–334 (2003).
Castle, J. D., Guo, Z. & Liu, L. Function of the t-SNARE SNAP-23 and secretory carrier membrane proteins (SCAMPs) in exocytosis in mast cells. Mol. Immunol. 38, 1337–1340 (2002).
Schafer, T., Starkl, P., Allard, C., Wolf, R. M. & Schweighoffer, T. A granular variant of CD63 is a regulator of repeated human mast cell degranulation. Allergy 65, 1242–1255 (2010).
Tuvim, M. J. et al. Rab3D, a small GTPase, is localized on mast cell secretory granules and translocates to the plasma membrane upon exocytosis. Am. J. Respir. Cell. Mol. Biol. 20, 79–89 (1999).
Azouz, N. P., Matsui, T., Fukuda, M. & Sagi-Eisenberg, R. Decoding the regulation of mast cell exocytosis by networks of Rab GTPases. J. Immunol. 189, 2169–2180 (2012).
Ushio, H. et al. Crucial role for autophagy in degranulation of mast cells. J. Allergy Clin. Immunol. 127, 1267–1276 e1266 (2011).
Raposo, G. et al. Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol. Biol. Cell 8, 2631–2645 (1997).
Bashkin, P., Razin, E., Eldor, A. & Vlodavsky, I. Degranulating mast cells secrete an endoglycosidase that degrades heparan sulfate in subendothelial extracellular matrix. Blood 75, 2204–2212 (1990).
Di 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. 180, 7565–7573 (2008).
Hunt, J. E. et al. Natural disruption of the mouse mast cell protease 7 gene in the C57BL/6 mouse. J. Biol. Chem. 271, 2851–2855 (1996).
Chen, L. Y. et al. Transgenic study of the function of chymase in heart remodeling. J. Hypertens. 20, 2047–2055 (2002).
Walther, D. J. et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76 (2003).
Kozma, G. T. et al. Histamine deficiency in gene-targeted mice strongly reduces antigen-induced airway hyper-responsiveness, eosinophilia and allergen-specific IgE. Int. Immunol. 15, 963–973 (2003).
Musio, S. et al. A key regulatory role for histamine in experimental autoimmune encephalomyelitis: disease exacerbation in histidine decarboxylase-deficient mice. J. Immunol. 176, 17–26 (2006).
The authors are supported by grants from The Swedish Research Council (G.P. and S.W.), The Swedish Cancer Foundation (G.P.), The Swedish Heart and Lung Foundation (G.P.) and Formas, Sweden (G.P.).
The authors declare no competing financial interests.
Serine proteases that have trypsin-like cleavage specificities — that is, they cleave peptide bonds on the carboxy-terminal side of arginine or lysine residues.
Serine proteases that have chymotrypsin-like cleavage specificities — that is, they cleave peptide bonds on the carboxy-terminal side of aromatic amino acid residues.
- Beige mice
A strain of mice with beige hair and a mutation in the gene that encodes lysosomal trafficking regulator (Lyst). These mice have an autosomal recessive disorder that is characterized by hypopigmentation and immune cell dysfunction. The phenotype of beige mice results from aberrant lysosomal trafficking and is similar to that of patients with Chediak–Higashi syndrome.
Rights and permissions
About this article
Cite this article
Wernersson, S., Pejler, G. Mast cell secretory granules: armed for battle. Nat Rev Immunol 14, 478–494 (2014). https://doi.org/10.1038/nri3690
This article is cited by
Role of GRPR in Acupuncture Intervention in the “Itch-scratch Vicious Cycle” Spinal Circuit of Chronic Pruritus
Chinese Medicine (2023)
IL-33-mediated activation of mast cells is involved in the progression of imiquimod-induced psoriasis-like dermatitis
Cell Communication and Signaling (2023)
Exocytic machineries differentially control mediator release from allergen-triggered RBL-2H3 cells
Inflammation Research (2023)
The molecular mechanisms of remodeling in asthma, COPD and IPF with a special emphasis on the complex role of Wnt5A
Inflammation Research (2023)
scRNA-seq generates a molecular map of emerging cell subtypes after sciatic nerve injury in rats
Communications Biology (2022)