Interleukin (IL)–36α, IL-36β, and IL-36γ are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (T_H17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associated with the disease in genome-wide studies. Next, we investigated the impact of in vivo and ex vivo IL-36 receptor blockade using a neutralizing antibody or a recombinant antagonist. Both inhibitors had marked anti-inflammatory effects on psoriatic skin, demonstrated by statistically significant reductions in IL-17 expression, keratinocyte activation, and leukocyte infiltration. Finally, we explored the potential safety profile associated with IL-36 blockade by phenotyping 12 individuals carrying knockout mutations of the IL-36 receptor gene. We found that normal immune function was broadly preserved in these individuals, suggesting that IL-36 signaling inhibition would not substantially compromise host defenses. These observations, which integrate the results of transcriptomics and model system analysis, pave the way for early-stage clinical trials of IL-36 antagonists.

白细胞介素 (IL)–36α、IL-36β 和 IL-36γ 是急性上皮炎症的先天介质。我们试图证明这些细胞因子也是斑块状银屑病的发病机制所必需的，斑块状银屑病是一种常见的慢性皮肤病，由异常 T 辅助细胞 17 (T _H17) 细胞活化。为了研究这种可能性，我们首先定义了由原代人角质形成细胞中的 IL-36 细胞因子诱导的基因。这使我们能够在全基因组研究中在斑块型银屑病中上调的转录本和与该疾病相关的易感基因座中证明显着的 IL-36 特征。接下来，我们使用中和抗体或重组拮抗剂研究了体内和体外 IL-36 受体阻断的影响。两种抑制剂都对银屑病皮肤具有显着的抗炎作用，这可以通过 IL-17 表达、角质形成细胞活化和白细胞浸润的统计学显着降低来证明。最后，我们通过对 12 名携带 IL-36 受体基因敲除突变的个体进行表型分析，探索了与 IL-36 阻断相关的潜在安全性。我们发现这些个体的正常免疫功能广泛保留，这表明 IL-36 信号抑制不会显着损害宿主防御。这些观察结果整合了转录组学和模型系统分析的结果，为 IL-36 拮抗剂的早期临床试验铺平了道路。