Mast Cells Are Dispensable in a Genetic Mouse Model of Chronic Dermatitis
2015; Elsevier BV; Volume: 185; Issue: 6 Linguagem: Inglês
10.1016/j.ajpath.2015.02.005
ISSN1525-2191
AutoresJitka Šulcová, Michaël Meyer, Eva Guiducci, Thorsten B. Feyerabend, Hans-Reimer Rodewald, Sabine Werner,
Tópico(s)Urticaria and Related Conditions
ResumoChronic inflammatory skin diseases, such as atopic dermatitis, affect a large percentage of the population, but the role of different immune cells in the pathogenesis of these disorders is largely unknown. Recently, we found that mice lacking fibroblast growth factor receptor 1 (Fgfr1) and Fgfr2 (K5-R1/R2 mice) in the epidermis have a severe impairment in the epidermal barrier, which leads to the development of a chronic inflammatory skin disease that shares many features with human atopic dermatitis. Using Fgfr1-/Fgfr2-deficient mice, we analyzed the consequences of the loss of mast cells. Mast cells accumulated and degranulated in the skin of young Fgfr1-/Fgfr2-deficient mice, most likely as a consequence of increased expression of the mast cell chemokine Ccl2. The increase in mast cells occurred before the development of histological abnormalities, indicating a functional role of these cells in the inflammatory skin phenotype. To test this hypothesis, we mated the Fgfr1-/Fgfr2-deficient mice with mast cell–deficient CreMaster mice. Surprisingly, loss of mast cells did not or only mildly affect keratinocyte proliferation, epidermal thickness, epidermal barrier function, accumulation and activation of different immune cells, or expression of different proinflammatory cytokines in the skin. These results reveal that mast cells are dispensable for the development of chronic inflammation in response to a defect in the epidermal barrier. Chronic inflammatory skin diseases, such as atopic dermatitis, affect a large percentage of the population, but the role of different immune cells in the pathogenesis of these disorders is largely unknown. Recently, we found that mice lacking fibroblast growth factor receptor 1 (Fgfr1) and Fgfr2 (K5-R1/R2 mice) in the epidermis have a severe impairment in the epidermal barrier, which leads to the development of a chronic inflammatory skin disease that shares many features with human atopic dermatitis. Using Fgfr1-/Fgfr2-deficient mice, we analyzed the consequences of the loss of mast cells. Mast cells accumulated and degranulated in the skin of young Fgfr1-/Fgfr2-deficient mice, most likely as a consequence of increased expression of the mast cell chemokine Ccl2. The increase in mast cells occurred before the development of histological abnormalities, indicating a functional role of these cells in the inflammatory skin phenotype. To test this hypothesis, we mated the Fgfr1-/Fgfr2-deficient mice with mast cell–deficient CreMaster mice. Surprisingly, loss of mast cells did not or only mildly affect keratinocyte proliferation, epidermal thickness, epidermal barrier function, accumulation and activation of different immune cells, or expression of different proinflammatory cytokines in the skin. These results reveal that mast cells are dispensable for the development of chronic inflammation in response to a defect in the epidermal barrier. A large percentage of the population has the chronic inflammatory skin disease atopic dermatitis (AD). This disease affects adults and children with worldwide prevalence rates of 1% to 20%, and the incidence has increased twofold to threefold during the last 40 years.1DaVeiga S.P. Epidemiology of atopic dermatitis: a review.Allergy Asthma Proc. 2012; 33: 227-234Crossref PubMed Scopus (170) Google Scholar External challenges, such as exposure to allergens, irritants, and pathogens and/or genetic or epigenetic alterations in genes that are expressed in keratinocytes, can lead to skin damage, disruption of its barrier function, and subsequent development of AD. In particular, mutations that lead to a defect in the epidermal barrier strongly increase the risk of AD development. Thus, up to 15% of all patients and up to 50% of patients with severe disease have mutations in the gene encoding filaggrin, a structural protein of the epidermis.2Brown S.J. McLean W.H. Eczema genetics: current state of knowledge and future goals.J Invest Dermatol. 2009; 129: 543-552Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 3Nomura T. Sandilands A. Akiyama M. Liao H. Evans A.T. Sakai K. Ota M. Sugiura H. Yamamoto K. Sato H. Palmer C.N. Smith F.J. McLean W.H. 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Thus, we recently found that loss of fibroblast growth factor receptor 1 (Fgfr1) and Fgfr2 in keratinocytes in mice caused a severe defect in the epidermal barrier. This phenotype was at least in part the consequence of reduced expression of major tight junction components, which are up-regulated in keratinocytes of normal mice by dermally derived Fgfs, in particular Fgf7 and Fgf10.10Yang J. Meyer M. Muller A.K. Bohm F. Grose R. Dauwalder T. Verrey F. Kopf M. Partanen J. Bloch W. Ornitz D.M. Werner S. Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis.J Cell Biol. 2010; 188: 935-952Crossref PubMed Scopus (104) Google Scholar The down-regulation of tight junction proteins in the Fgfr mutant mice (designated K5-R1/R2 mice) caused functional deficits of these junctions, and the mice developed a phenotype, which shares various features with the abnormalities observed in flaky tail mice (mutations in the filaggrin and matted genes)11Fallon P.G. Sasaki T. Sandilands A. Campbell L.E. Saunders S.P. Mangan N.E. Callanan J.J. Kawasaki H. Shiohama A. Kubo A. Sundberg J.P. Presland R.B. Fleckman P. Shimizu N. Kudoh J. Irvine A.D. Amagai M. McLean W.H. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (376) Google Scholar, 12Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. Campbell L.E. Gierlinski M. Barton G.J. Schneider G. Balmain A. Prescott A.R. Weidinger S. Baurecht H. Kabesch M. Gieger C. Lee Y.A. Tavendale R. Mukhopadhyay S. Turner S.W. Madhok V.B. Sullivan F.M. Relton C. Burn J. Meggitt S. Smith C.H. Allen M.A. Barker J.N. Reynolds N.J. Cordell H.J. Irvine A.D. McLean W.H. Sandilands A. Fallon P.G. Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 13Scharschmidt T.C. Man M.Q. Hatano Y. Crumrine D. Gunathilake R. Sundberg J.P. Silva K.A. Mauro T.M. Hupe M. Cho S. Wu Y. Celli A. Schmuth M. Feingold K.R. Elias P.M. Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.J Allergy Clin Immunol. 2009; 124 (506.e1–6): 496-506Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar and in patients with chronic AD (Table 1). Consistent with our findings, down-regulation of FGFR1 and FGFR2 expression was detected in the skin of AD patients,14Guttman-Yassky E. Suarez-Farinas M. Chiricozzi A. Nograles K.E. Shemer A. Fuentes-Duculan J. Cardinale I. Lin P. Bergman R. Bowcock A.M. Krueger J.G. Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis.J Allergy Clin Immunol. 2009; 124: 1235-1244.e58Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar and single-nucleotide polymorphisms in the FGFR1 and FGFR2 genes were linked to atopy.15Park H.K. Park H.W. Jeon S.G. Shin E.S. Gho Y.S. Cho S.H. Kim Y.Y. Kim Y.K. 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Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis.J Cell Biol. 2010; 188: 935-952Crossref PubMed Scopus (104) Google ScholarEpidermal thickness↑18Kiehl P. Falkenberg K. Vogelbruch M. Kapp A. Tissue eosinophilia in acute and chronic atopic dermatitis: a morphometric approach using quantitative image analysis of immunostaining.Br J Dermatol. 2001; 145: 720-729Crossref PubMed Scopus (89) Google Scholar, 19Dumortier A. Durham A.D. Di Piazza M. Vauclair S. Koch U. Ferrand G. Ferrero I. Demehri S. Song L.L. Farr A.G. Leonard W.J. Kopan R. Miele L. Hohl D. Finke D. Radtke F. Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin.PLoS One. 2010; 5: e9258Crossref PubMed Scopus (139) Google Scholar, 20Yang G.Y. Chen X. Sun Y.C. Ma C.L. Qian G. 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Callanan J.J. Kawasaki H. Shiohama A. Kubo A. Sundberg J.P. Presland R.B. Fleckman P. Shimizu N. Kudoh J. Irvine A.D. Amagai M. McLean W.H. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (376) Google Scholar, 13Scharschmidt T.C. Man M.Q. Hatano Y. Crumrine D. Gunathilake R. Sundberg J.P. Silva K.A. Mauro T.M. Hupe M. Cho S. Wu Y. Celli A. Schmuth M. Feingold K.R. Elias P.M. Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.J Allergy Clin Immunol. 2009; 124 (506.e1–6): 496-506Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 22Oyoshi M.K. Murphy G.F. Geha R.S. Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen.J Allergy Clin Immunol. 2009; 124 (493.e1): 485-493Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 23Leisten S. Oyoshi M.K. Galand C. Hornick J.L. Gurish M.F. Geha R.S. Development of skin lesions in filaggrin-deficient mice is dependent on adaptive immunity.J Allergy Clin Immunol. 2013; 131 (1250.e1): 1247-1250Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar↑10Yang J. Meyer M. Muller A.K. Bohm F. Grose R. Dauwalder T. Verrey F. Kopf M. Partanen J. Bloch W. Ornitz D.M. Werner S. Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis.J Cell Biol. 2010; 188: 935-952Crossref PubMed Scopus (104) Google ScholarMast cells↑33Damsgaard T.E. Olesen A.B. Sorensen F.B. Thestrup-Pedersen K. Schiotz P.O. Mast cells and atopic dermatitis. Stereological quantification of mast cells in atopic dermatitis and normal human skin.Arch Dermatol Res. 1997; 289: 256-260Crossref PubMed Scopus (74) Google Scholar, 34Kawakami T. Ando T. Kimura M. Wilson B.S. Kawakami Y. Mast cells in atopic dermatitis.Curr Opin Immunol. 2009; 21: 666-678Crossref PubMed Scopus (237) Google Scholar↑17Moniaga C.S. Egawa G. Kawasaki H. Hara-Chikuma M. Honda T. Tanizaki H. Nakajima S. Otsuka A. Matsuoka H. Kubo A. Sakabe J. Tokura Y. Miyachi Y. Amagai M. Kabashima K. Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus extract.Am J Pathol. 2010; 176: 2385-2393Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar↑10Yang J. Meyer M. Muller A.K. Bohm F. Grose R. Dauwalder T. Verrey F. Kopf M. Partanen J. Bloch W. Ornitz D.M. Werner S. Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis.J Cell Biol. 2010; 188: 935-952Crossref PubMed Scopus (104) Google ScholarFlaky tail mice, which have mutations in the filaggrin and matted genes,12Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. Campbell L.E. Gierlinski M. Barton G.J. Schneider G. Balmain A. Prescott A.R. Weidinger S. Baurecht H. Kabesch M. Gieger C. Lee Y.A. Tavendale R. Mukhopadhyay S. Turner S.W. Madhok V.B. Sullivan F.M. Relton C. Burn J. Meggitt S. Smith C.H. Allen M.A. Barker J.N. Reynolds N.J. Cordell H.J. Irvine A.D. McLean W.H. Sandilands A. Fallon P.G. Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar were included in the comparison because they represent an established mouse model for atopic dermatitis.11Fallon P.G. Sasaki T. Sandilands A. Campbell L.E. Saunders S.P. Mangan N.E. Callanan J.J. Kawasaki H. Shiohama A. Kubo A. Sundberg J.P. Presland R.B. Fleckman P. Shimizu N. Kudoh J. Irvine A.D. Amagai M. McLean W.H. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (376) Google Scholar Parameters analyzed include transepidermal water loss, epidermal thickening, serum levels of IgE and IgG, and number of epidermal γδ T cells, αβ T cells, Langerhans cells, dermal neutrophils, eosinophils, T cells, and mast cells. Arrow indicates an increase in a particular parameter. Open table in a new tab Flaky tail mice, which have mutations in the filaggrin and matted genes,12Saunders S.P. Goh C.S. Brown S.J. Palmer C.N. Porter R.M. Cole C. Campbell L.E. Gierlinski M. Barton G.J. Schneider G. Balmain A. Prescott A.R. Weidinger S. Baurecht H. Kabesch M. Gieger C. Lee Y.A. Tavendale R. Mukhopadhyay S. Turner S.W. Madhok V.B. Sullivan F.M. Relton C. Burn J. Meggitt S. Smith C.H. Allen M.A. Barker J.N. Reynolds N.J. Cordell H.J. Irvine A.D. McLean W.H. Sandilands A. Fallon P.G. Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects.J Allergy Clin Immunol. 2013; 132: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar were included in the comparison because they represent an established mouse model for atopic dermatitis.11Fallon P.G. Sasaki T. Sandilands A. Campbell L.E. Saunders S.P. Mangan N.E. Callanan J.J. Kawasaki H. Shiohama A. Kubo A. Sundberg J.P. Presland R.B. Fleckman P. Shimizu N. Kudoh J. Irvine A.D. Amagai M. McLean W.H. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (376) Google Scholar Parameters analyzed include transepidermal water loss, epidermal thickening, serum levels of IgE and IgG, and number of epidermal γδ T cells, αβ T cells, Langerhans cells, dermal neutrophils, eosinophils, T cells, and mast cells. Arrow indicates an increase in a particular parameter. Because most studies found increased numbers of mast cells in skin lesions of patients with AD, it is generally assumed that mast cells contribute to the development and/or maintenance of skin inflammation in these patients.33Damsgaard T.E. Olesen A.B. Sorensen F.B. Thestrup-Pedersen K. Schiotz P.O. Mast cells and atopic dermatitis. Stereological quantification of mast cells in atopic dermatitis and normal human skin.Arch Dermatol Res. 1997; 289: 256-260Crossref PubMed Scopus (74) Google Scholar, 34Kawakami T. Ando T. Kimura M. Wilson B.S. Kawakami Y. Mast cells in atopic dermatitis.Curr Opin Immunol. 2009; 21: 666-678Crossref PubMed Scopus (237) Google Scholar Mast cells are particularly abundant at the host’s interface with the environment, such as the skin or mucosae. They are long-lived cells, which proliferate in response to appropriate stimuli.35Abraham S.N. Malaviya R. Mast cells in infection and immunity.Infect Immun. 1997; 65: 3501-3508PubMed Google Scholar They express a high-affinity FcεRI receptor that strongly binds IgE antibodies. Interestingly, the latter are abundant in the skin and the serum of K5-R1/R2 mice and of AD patients (Table 1). On binding of allergens to mast cell–bound IgE, degranulation of mast cells occurs, resulting in release of bioactive molecules stored in granules, including histamine, heparin, different proteases, and proinflammatory cytokines. This causes vessel dilatation, local edema, activation of other immune cells, and inflammation.36Abraham S.N. St John AL: mast cell-orchestrated immunity to pathogens.Nat Rev Immunol. 2010; 10: 440-452Crossref PubMed Scopus (694) Google Scholar Previous studies37Alenius H. Laouini D. Woodward A. Mizoguchi E. Bhan A.K. Castigli E. Oettgen H.C. Geha R.S. Mast cells regulate IFN-gamma expression in the skin and circulating IgE levels in allergen-induced skin inflammation.J Allergy Clin Immunol. 2
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