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Review article: Biomedical intelligence

Vol. 144 No. 3536 (2014)

Beyond allergy: the role of mast cells in fibrosis

  • Thomas Hügle
DOI
https://doi.org/10.4414/smw.2014.13999
Cite this as:
Swiss Med Wkly. 2014;144:w13999
Published
24.08.2014

Summary

Mast cells are tissue-bound cells of the innate immune system which are well known for immunoglobuline (Ig)E-triggered degranulation in allergic reactions. More recently, an important role of mast cells has been described in chronic inflammatory and autoimmune disorders which are often associated with fibrosis or sclerosis. Innate immune receptors such as Fc-, toll-like- or NOD-like receptors stimuli can trigger mast cell degranulation and enhance immunological danger signals. Whereas fulminant degranulation of mast cell vesicles is observed in anaphylaxis, piecemeal degranulation or transgranulation are mechanisms for a slower release of their granula. A cocktail of cytokines, growth factors and proteoglycans is produced and stored in granula of mast cells. Mast cells are a substantial reservoir of both preformed inflammatory factors (i.e., TNF-alpha and IL-17) and factors that can trigger a profibrotic, Th-2–polarised inflammation (i.e., IL-4 and IL-10). In systemic sclerosis, mast cell vesicles are the main source of transforming growth factor (TGF)-beta. Cell-to-cell contact between mast cells and fibroblasts occurs in the affected tissue, supporting the hypothesis that transgranulation might be an important mechanism in fibrosis. The direct release of proteoglycans such as hyaluronic acid into the interstitial space is a further stimulus for matrix remodelling. Mast cell hyperactivity has also been demonstrated in primary fibrotic disorders such as lung, cardiac or renal fibrosis. The exact trigger for mast cell degranulation however is not known. Notwithstanding, at a very early time point of fibrosis, mast cell inhibition by stabilisers or blockage of the tyrosine kinase receptor c-kit by masitinib could be a therapeutic option.

References

  1. Ehrlich P. Beiträge zur Kenntnis der Anilinfärbungen und ihrer Verwendung in der mikroskopischen Technik. Archiv fuer mikroskopische Anatomie. 1877;13:263–78.
  2. Kitamura Y, Tamai M, Miyano Y, Shimada M. Development of hematopoietic spleen colonies in nonirradiated genetically normal mice. Blood. 1977;50(6):1121–7.
  3. Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13). Blood. 1999;94(7):2333–42.
  4. Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8(3):205–17.
  5. Prussin C, Metcalfe DD. 4. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2003;111(2 Suppl):S486–S494.
  6. Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Munoz-Planillo R, Hasegawa M, et al. Staphylococcus delta-toxin induces allergic skin disease by activating mast cells. Nature. 2013;503(7476):397–401.
  7. Dvorak AM, Kissell S. Granule changes of human skin mast cells characteristic of piecemeal degranulation and associated with recovery during wound healing in situ. J Leukoc Biol. 1991;49(2):197–210.
  8. Wang HW, Tedla N, Lloyd AR, Wakefield D, McNeil PH. Mast cell activation and migration to lymph nodes during induction of an immune response in mice. J Clin Invest. 1998;102(8):1617–26.
  9. Sandig H, Bulfone-Paus S. TLR signaling in mast cells: common and unique features. Front Immunol. 2012;3:185.
  10. Zhang D, Spielmann A, Wang L, Ding G, Huang F, Gu Q, et al. Mast-cell degranulation induced by physical stimuli involves the activation of transient-receptor-potential channel TRPV2. Physiol Res. 2012;61(1):113–24.
  11. Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, et al. Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol. 2010;184(7):3336–40.
  12. Claman HN. On scleroderma. Mast cells, endothelial cells, and fibroblasts. JAMA. 1989;262(9):1206–9.
  13. Andrade ZA. Schistosomiasis and liver fibrosis. Parasite Immunol. 2009;31(11):656–63.
  14. Sabin EA, Kopf MA, Pearce EJ. Schistosoma mansoni egg-induced early IL-4 production is dependent upon IL-5 and eosinophils. J Exp Med. 1996;184(5):1871–8.
  15. Taipale J, Lohi J, Saarinen J, Kovanen PT, Keski-Oja J. Human mast cell chymase and leukocyte elastase release latent transforming growth factor-beta 1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem. 1995;270(9):4689–96.
  16. Eggli PS, Graber W. Cytochemical localization of hyaluronan in rat and human skin mast cell granules. J Invest Dermatol. 1993;100(2):121–5.
  17. Trautmann A, Toksoy A, Engelhardt E, Brocker EB, Gillitzer R. Mast cell involvement in normal human skin wound healing: expression of monocyte chemoattractant protein-1 is correlated with recruitment of mast cells which synthesize interleukin-4 in vivo. J Pathol. 2000;190(1):100–6.
  18. Takato H, Yasui M, Ichikawa Y, Waseda Y, Inuzuka K, Nishizawa Y, et al. The specific chymase inhibitor TY-51469 suppresses the accumulation of neutrophils in the lung and reduces silica-induced pulmonary fibrosis in mice. Exp Lung Res. 2011;37(2):101–8.
  19. Weller CL, Collington SJ, Brown JK, Miller HR, Al-Kashi A, Clark P, et al. Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors. J Exp Med. 2005;201(12):1961–71.
  20. Gailit J, Marchese MJ, Kew RR, Gruber BL. The differentiation and function of myofibroblasts is regulated by mast cell mediators. J Invest Dermatol. 2001;117(5):1113–9.
  21. Ehrlich HP. A Snapshot of Direct Cell-Cell Communications in Wound Healing and Scarring. Adv Wound Care. (New Rochelle) 2013;2(4):113–21.
  22. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2013;71:549–74.
  23. Hara M, Ono K, Hwang MW, Iwasaki A, Okada M, Nakatani K, et al. Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med. 2002;195(3):375–81.
  24. Levick SP, McLarty JL, Murray DB, Freeman RM, Carver WE, Brower GL. Cardiac mast cells mediate left ventricular fibrosis in the hypertensive rat heart. Hypertension. 2009;53(6):1041–7.
  25. Roberts IS, Brenchley PE. Mast cells: the forgotten cells of renal fibrosis. J Clin Pathol. 2000;53(11):858–62.
  26. Ishida T, Hyodo Y, Ishimura T, Takeda M, Hara I, Fujisawa M. Mast cell numbers and protease expression patterns in biopsy specimens following renal transplantation from living-related donors predict long-term graft function. Clin Transplant. 2005;19(6):817–24.
  27. Tuder RM. A pathologist’s approach to interstitial lung disease. Curr Opin Pulm Med. 1996;2(5):357–63.
  28. Pesci A, Bertorelli G, Gabrielli M, Olivieri D. Mast cells in fibrotic lung disorders. Chest. 1993;103(4):989–96.
  29. Hirata K, Sugama Y, Ikura Y, Ohsawa M, Inoue Y, Yamamoto S, et al. Enhanced mast cell chymase expression in human idiopathic interstitial pneumonia. Int J Mol Med. 2007;19(4):565–70.
  30. Veerappan A, O'Connor NJ, Brazin J, Reid AC, Jung A, McGee D, et al. Mast cells: a pivotal role in pulmonary fibrosis. DNA Cell Biol. 2013;32(4):206–18.
  31. Fireman E, Kivity S, Shahar I, Reshef T, Mekori YA. Secretion of stem cell factor by alveolar fibroblasts in interstitial lung diseases. Immunol Lett. 1999;67(3):229–36.
  32. Wygrecka M, Dahal BK, Kosanovic D, Petersen F, Taborski B, von GS, et al. Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: role of transmembrane SCF and the PAR-2/PKC-alpha/Raf-1/p44/42 signaling pathway. Am J Pathol. 2013;182(6):2094–108.
  33. Hirata K, Sugama Y, Ikura Y, Ohsawa M, Inoue Y, Yamamoto S, et al. Enhanced mast cell chymase expression in human idiopathic interstitial pneumonia. Int J Mol Med. 2007;19(4):565–70.
  34. Piconese S, Gri G, Tripodo C, Musio S, Gorzanelli A, Frossi B, et al. Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17–cell differentiation. Blood. 2009;114(13):2639–48.
  35. Merluzzi S, Betto E, Ceccaroni AA, Magris R, Giunta M, Mion F. Mast cells, basophils and B cell connection network. Mol Immunol. 2014;S0161–5890(14)00050–9:Epub ahead of print.
  36. Hawkins RA, Claman HN, Clark RA, Steigerwald JC. Increased dermal mast cell populations in progressive systemic sclerosis: a link in chronic fibrosis? Ann Intern Med. 1985;102(2):182–6.
  37. Hugle T, Hogan V, White KE, van Laar JM. Mast cells are a source of transforming growth factor beta in systemic sclerosis. Arthritis Rheum. 2011;63(3):795–9.
  38. Trautmann A, Krohne G, Brocker EB, Klein CE. Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4. J Immunol. 1998;160(10):5053–7.
  39. Hugle T, White K, van Laar JM. Cell-to-cell contact of activated mast cells with fibroblasts and lymphocytes in systemic sclerosis. Ann Rheum Dis. 2012;71:1582.
  40. Binai N, O’Reilly S, Griffiths B, van Laar JM, Hugle T. Differentiation potential of CD14+ monocytes into myofibroblasts in patients with systemic sclerosis. PLoS One 2012;7(3):e33508.
  41. Monument MJ, Hart DA, Befus AD, Salo PT, Zhang M, Hildebrand KA. The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures. Inflamm Res. 2012;61(4):285–92.
  42. Walker M, Harley R, LeRoy EC. Ketotifen prevents skin fibrosis in the tight skin mouse. J Rheumatol. 1990;17(1):57–9.
  43. Walker MA, Harley RA, LeRoy EC. Inhibition of fibrosis in TSK mice by blocking mast cell degranulation. J Rheumatol. 1987;14(2):299–301.
  44. Gruber BL, Kaufman LD. A double-blind randomized controlled trial of ketotifen versus placebo in early diffuse scleroderma. Arthritis Rheum. 1991;34(3):362–6.
  45. Beyer C, Distler JH, Distler O. Are tyrosine kinase inhibitors promising for the treatment of systemic sclerosis and other fibrotic diseases? Swiss Med Wkly. 2010;140:w13050.
  46. Maurer B, Distler A, Dees C, Khan K, Denton CP, Abraham D, et al. Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors. Ann Rheum Dis. 2013;72(12):2039–46.

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