期刊
JOURNAL OF IMMUNOLOGY
卷 199, 期 2, 页码 707-717出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1602185
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资金
- Wellcome Trust [092530/Z/10/Z]
- National Children's Research Centre
- Science Foundation Ireland [10/IN.1/B3004]
- EMBO long term fellowship [ALTF 587-2016]
- Irish Research Council fellowship
- Biotechnology and Biological Sciences Research Council [BB/J01026X/1] Funding Source: researchfish
- Medical Research Council [MC_UU_12010/5, MC_U105178805, MC_U137881017, G1000800h] Funding Source: researchfish
- BBSRC [BB/J01026X/1] Funding Source: UKRI
- MRC [MC_U105178805, MC_U137881017, MC_UU_12010/5] Funding Source: UKRI
- Science Foundation Ireland (SFI) [10/IN.1/B3004] Funding Source: Science Foundation Ireland (SFI)
Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children and 3% of adults worldwide and is associated with dysregulation of the skin barrier. Although type 2 responses are implicated in AD, emerging evidence indicates a potential role for the IL-17A signaling axis in AD pathogenesis. In this study we show that in the filaggrin mutant mouse model of spontaneous AD, IL-17RA deficiency (Il17ra(-/-)) resulted in severe exacerbation of skin inflammation. Interestingly, Il17ra(-/-) mice without the filaggrin mutation also developed spontaneous progressive skin inflammation with eosinophilia, as well as increased levels of thymic stromal lymphopoietin (TSLP) and IL-5 in the skin. Il17ra(-/-) mice have a defective skin barrier with altered filaggrin expression. The barrier dysregulation and spontaneous skin inflammation in Il17ra(-/-) mice was dependent on TSLP, but not the other alarmins IL-25 and IL-33. The associated skin inflammation was mediated by IL-5-expressing pathogenic effector Th2 cells and was independent of TCR gamma delta T cells and IL-22. An absence of IL-17RA in nonhematopoietic cells, but not in the hematopoietic cells, was required for the development of spontaneous skin inflammation. Skin microbiome dysbiosis developed in the absence of IL-17RA, with antibiotic intervention resulting in significant amelioration of skin inflammation and reductions in skin-infiltrating pathogenic effector Th2 cells and TSLP. This study describes a previously unappreciated protective role for IL-17RA signaling in regulation of the skin barrier and maintenance of skin immune homeostasis.
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