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Interleukin-17 receptor A maintains and protects the skin barrier to prevent allergic skin inflammation

机译:白介素17受体A维持并保护皮肤屏障防止过敏性皮肤发炎

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摘要

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. While type 2 responses are implicated in AD, emerging evidence indicates potential role for the IL-17A signalling 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, 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 (pe) Th2 cells and was independent of TCRγδ T cells and IL-22. An absence of IL-17RA in non-hematopoietic 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 peTh2 cells and TSLP. This study describes a previously unappreciated protective role for IL-17RA signalling in regulation of the skin barrier and maintenance of skin immune homeostasis.
机译:特应性皮炎(AD)是一种常见的炎症性皮肤病,影响全世界多达20%的儿童和3%的成年人,并与皮肤屏障的失调有关。虽然2型反应与AD有关,但新兴证据表明IL-17A信号转导轴在AD发病机理中的潜在作用。在这项研究中,我们表明在自发性AD的丝聚蛋白突变小鼠模型中,IL-17RA缺乏症(Il17ra -/-)导致皮肤炎症的严重加重。有趣的是,没有丝聚蛋白突变的Il17ra -/-小鼠也发生了自发进行性皮肤炎症和嗜酸性粒细胞增多,胸腺基质淋巴细胞生成素(TSLP)和IL-5水平升高。 Il17ra -/-小鼠的皮肤屏障缺陷,丝聚蛋​​白表达改变。 Il17ra -/-小鼠的屏障失调和自发性皮肤发炎依赖于TSLP,但不依赖于其他警报蛋白IL-25和IL-33。相关的皮肤炎症是由表达IL-5的致病性效应(pe)Th2细胞介导的,并且独立于TCRγδT细胞和IL-22。自发性皮肤发炎需要在非造血细胞中但在造血细胞中不存在IL-17RA。在没有IL-17RA的情况下出现皮肤微生物组营养不良,并通过抗生素干预导致皮肤炎症明显改善,皮肤浸润性peTh2细胞和TSLP减少。这项研究描述了IL-17RA信号传导在调节皮肤屏障和维持皮肤免疫稳态方面前所未有的保护作用。

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