The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24
The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24
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DOI：
10.1016/j.immuni.2020.06.022
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发表时间：
2020-08-18
期刊：
影响因子：
32.4
通讯作者：
Caspi, Rachel R.
中科院分区：
文献类型：
--
作者：
Chong, Wai Po;Mattapallil, Mary J.;Caspi, Rachel R.
Th 17细胞应答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，在葡萄膜炎中靶向IL-17 A的临床试验并不成功。在这里，我们报告Th 17细胞受到其自身标志性细胞因子IL-17 A的调节。自体致病性Th 17细胞中IL 17 A的缺失并不降低其致病性，而是提高了其Th 17细胞因子GM-CSF和IL-17 F的表达。体外机制研究揭示了由IL-17 A与其受体结合触发的Th 17细胞内在自分泌环，导致转录因子NF-κ B的活化和IL-24的诱导，其抑制了Th 17细胞因子程序。在体内，IL-24治疗改善了Th 17诱导的EAU，而Th 17细胞中IL-24的沉默增强了疾病。这种调节途径也在人Th 17细胞中起作用。因此，IL-17 A通过诱导IL-24来限制Th 17细胞的致病性。这些发现可以解释靶向IL-17 A在葡萄膜炎中令人失望的治疗效果。
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 IL17A 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-kappa B 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.