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 - 29/03/12
, Gráinne M. O’Regan, MRCPI b, c, , René Lutter, PhD d, Ivone Jakasa, PhD a, e, Ellen S. Koster, PhD a, Sean Saunders, BSc b, j, Peter Caspers, PhD f, g, Patrick M.J.H. Kemperman, MD h, Gerwin J. Puppels, PhD f, g, Aileen Sandilands, PhD i, Huijia Chen, PhD i, Linda E. Campbell, BSc i, Karin Kroboth, MSc i, Rosemarie Watson, MD c, Padraic G. Fallon, PhD b, j, W. H. Irwin McLean, DSc, FMedSci i, Alan D. Irvine, MD, FRCPI b, c, j, ⁎ 
Corresponding author: Alan D. Irvine, MD, FRCPI, Paediatric Dermatology, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland.Abstract |
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 (ADFLG) compared with that seen in patients with AD without these mutations (ADNON-FLG).
Objectives |
We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with ADFLG versus patients with ADNON-FLG. We also sought to examine the same profiles in a murine model of filaggrin deficiency (Flgft/Flgft [FlgdelAPfal] 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⍺, IL-1β, 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. Flgft/Flgft (FlgdelAPfal) mice, separated from maFlgft/maFlgft (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⍺, IL-1β, and IL-1RA.
Results |
SC IL-1 levels were increased in patients with ADFLG; these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flgft/Flgft mice had upregulated expression of IL-1β and IL-1RA mRNA.
Conclusions |
ADFLG 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.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, confocal Raman spectroscopy, eczema, filaggrin, natural moisturizing factor, pH, transepidermal water loss, IL-1, IL-18, skin barrier, FLG gene mutations, Flgft/Flgft (FlgdelAPfal) mice
Abbreviations used : AD, ADFLG, ADNON-FLG, FLG, FLG−/−, FLG+/−, FLG+/+, IL-1RA, NESS, NMF, SC, TEWL
Plan
| Supported by COST Action BM0903 (SKINBAD). P.C. and G.J.P. are employees of River Diagnostics BV, Rotterdam, The Netherlands. A.D.I. and G.M.O. are supported by the National Children’s Research Centre, Dublin. Filaggrin research in the McLean laboratory is supported by grants from the British Skin Foundation, the National Eczema Society, the Medical Research Council (G0700314), and donations from anonymous families affected by eczema in the Tayside Region of Scotland. A.D.I. and W.H.I.M. are supported by the Wellcome Trust (090066/B/09/Z and 092530/Z/10/Z). P.G.F. is supported by a research grant from the Wellcome Trust (092530/Z/10/Z). |
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| Disclosure of potential conflict of interest: G. M. O’Regan has received research support and is employed by the National Children’s Research Centre. P. G. Fallon has received research support from the Science Foundation, Ireland; the National Children’s Research Centre; and the Wellcome Trust. A. D. Irvine has received research support from the Wellcome Trust and National Children’s Research Centre. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 129 - N° 4
P. 1031 - avril 2012 Retour au numéro
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