State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China; Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
Immunity. 2020 Aug 18;53(2):384-397.e5. doi: 10.1016/j.immuni.2020.06.022. Epub 2020 Jul 15.
Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis were not successful. Here, we report that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of the transcription factor NF-κB and induction of IL-24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect of targeting IL-17A in uveitis.
Th17 细胞反应失调是多种炎症和自身免疫性疾病的基础，包括自身免疫性葡萄膜炎及其动物模型 EAU。然而，针对白介素-17A（IL-17A）在葡萄膜炎中的临床试验并未成功。在这里，我们报告称 Th17 细胞受其自身特征性细胞因子 IL-17A 调节。在自身致病性 Th17 细胞中缺失 IL-17A 并不会降低其致病性，反而会增加 Th17 细胞因子 GM-CSF 和 IL-17F 的表达。体外机制研究揭示了一个由 IL-17A 与其受体结合触发的 Th17 细胞内在自分泌环，导致转录因子 NF-κB 的激活和 IL-24 的诱导，后者抑制了 Th17 细胞因子程序。在体内，IL-24 治疗改善了 Th17 诱导的 EAU，而在 Th17 细胞中沉默 IL-24 则增强了疾病。这条调节途径也在人类 Th17 细胞中起作用。因此，IL-17A 通过诱导 IL-24 来限制 Th17 细胞的致病性。这些发现可能解释了针对 IL-17A 在葡萄膜炎中治疗效果不佳的原因。
