期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 129, 期 4, 页码 1031-U542出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2011.12.989
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
资金
- COST Action [BM0903]
- National Children's Research Centre, Dublin
- British Skin Foundation
- National Eczema Society
- Medical Research Council [G0700314]
- Tayside Region of Scotland
- Wellcome Trust [090066/B/09/Z, 092530/Z/10/Z]
- National Children's Research Centre
- Science Foundation, Ireland
- Wellcome Trust [090066/B/09/Z, 092530/Z/10/Z] Funding Source: Wellcome Trust
- MRC [G0700314] Funding Source: UKRI
- Medical Research Council [G0700314] Funding Source: researchfish
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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