IL-17 Receptor A Maintains and Protects the Skin Barrier To Prevent Allergic Skin Inflammation [INNATE IMMUNITY AND INFLAMMATION]

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 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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