Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:129

Article

Kezic, Sanja³  O'Regan, Grainne M.^1,2  Lutter, Rene^4,5  Jakasa, Ivone^3,6  Koster, Ellen S.³  Saunders, Sean^1,10  Caspers, Peter^7,8  Puppels, Gerwin J.^7,8  Sandilands, Aileen⁹  Chen, Huijia⁹  Campbell, Linda E.⁹  Kroboth, Karin⁹  Watson, Rosemarie²  Fallon, Padraic G.^1,10  McLean, W. H. Irwin⁹  Irvine, Alan D.^1,2,10 

[1] Our Ladys Childrens Hosp, Natl Childrens Res Ctr, Dublin 12, Ireland

[2] Our Ladys Childrens Hosp, Dept Paediat Dermatol, Dublin 12, Ireland

[3] Univ Amsterdam, Acad Med Ctr, Coronel Inst Occupat Hlth, NL-1105 AZ Amsterdam, Netherlands

[4] Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, NL-1105 AZ Amsterdam, Netherlands

[5] Univ Amsterdam, Acad Med Ctr, Dept Resp Med, NL-1105 AZ Amsterdam, Netherlands

[6] Univ Zagreb, Analyt Chem Lab, Dept Chem & Biochem, Fac Food Technol & Biotechnol, Zagreb 41000, Croatia

[7] Erasmus MC, Ctr Opt Diagnost & Therapy, Dept Dermatol, Rotterdam, Netherlands

[8] River Diagnost BV, Rotterdam, Netherlands

[9] Univ Dundee, Epithelial Genet Grp, Inst Med Sci, Dundee DD1 4HN, Scotland

[10] Univ Dublin Trinity Coll, Dept Med, Dublin 2, Ireland

关键词: Atopic dermatitis;    confocal Raman spectroscopy;    eczema;    filaggrin;    natural moisturizing factor;    pH;    transepidermal water loss;    IL-1;    IL-18;    skin barrier;    FLG gene mutations;    Flg(ft)/Flg(ft)(Flg(delAPfal)) mice;   

DOI  :  10.1016/j.jaci.2011.12.989

来源: Elsevier

【 摘 要 】

Background: Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD(FLG)) compared with that seen in patients with AD without these mutations (AD(NON-FLG)). Objectives: We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD(FLG) versus patients with AD(NON-FLG). We also sought to examine the same profiles in a murine model of filaggrin deficiency (Flg(ft)/Flg(ft) [Flg(delAPfal)] mice). Methods: One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1 alpha, IL-1 beta, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flg(ft)/Flg(ft) (Flg(delAPfal)) mice, separated from maFlg(ft)/maFlg(ft) (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1 alpha, IL-1 beta, and IL-1RA. Results: SC IL-1 levels were increased in patients with AD(FLG); these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flg(ft)/Flg(ft) mice had upregulated expression of IL-1 beta and IL-1RA mRNA. Conclusions: AD(FLG) is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches. (J Allergy Clin Immunol 2012;129:1031-9.)

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