AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production.
AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production.
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DOI：
10.1016/j.jid.2016.06.618
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Capon F
中科院分区：
文献类型：
--
作者：
Mahil SK;Twelves S;Farkas K;Setta-Kaffetzi N;Burden AD;Gach JE;Irvine AD;Képíró L;Mockenhaupt M;Oon HH;Pinner J;Ranki A;Seyger MMB;Soler-Palacin P;Storan ER;Tan ES;Valeyrie-Allanore L;Young HS;Trembath RC;Choon SE;Szell M;Bata-Csorgo Z;Smith CH;Di Meglio P;Barker JN;Capon F
显着的皮肤受累是由异常 IL-1 信号传导引起的自身炎症性疾病的一个定义特征。然而，驱动皮肤自身炎症特征的途径和细胞类型仍然知之甚少。我们试图通过研究脓疱型银屑病的发病机制来解决这个问题，脓疱型银屑病是一种以皮肤表现为主的自身炎症性疾病模型。我们特别描述了影响 AP1S3 的突变的影响，AP1S3 是我们小组先前鉴定的一种疾病基因，并在新确定的患者资源中进行了验证。我们首先表明 AP1S3 表达在角质形成细胞中显着升高。由于 AP1S3 编码一种与自噬体形成有关的蛋白质，因此我们接下来研究了基因沉默对该途径的影响。我们发现 AP1S3 敲除会破坏角质形成细胞自噬，导致 p62（介导 NF-κB 激活的接头蛋白）异常积累。我们发现，AP1S3 缺陷细胞会上调 IL-1 信号传导并过度表达 IL-36α（一种正在成为皮肤炎症重要介质的细胞因子）。这些异常的免疫特征通过药物自噬抑制得到重现，并在患者角质形成细胞中得到验证，IL-36 阻断可逆转这些异常的免疫特征。这些发现表明角质形成细胞在皮肤自身炎症中发挥关键作用，并将 IL-36 信号的自噬调节确定为治疗靶点。
Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.
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