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The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24.
Immunity ( IF 25.5 ) Pub Date : 2020-07-15 , DOI: 10.1016/j.immuni.2020.06.022
Wai Po Chong 1 , Mary J Mattapallil 2 , Kumarkrishna Raychaudhuri 2 , So Jin Bing 2 , Sihan Wu 3 , Yajie Zhong 3 , WeiWei Wang 3 , Zilin Chen 3 , Phyllis B Silver 2 , Yingyos Jittayasothorn 2 , Chi-Chao Chan 2 , Jun Chen 3 , Reiko Horai 2 , Rachel R Caspi 2
Affiliation  

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.



中文翻译:

细胞因子IL-17A通过IL-24自分泌诱导产生的负反馈回路限制Th17的致病性。

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。但是,针对葡萄膜炎中IL-17A的临床试验并不成功。在这里,我们报道Th17细胞受其自身的特征性细胞因子IL-17A调控。IL-17A在自身致病性Th17细胞中的丢失并未降低其致病性,而是提高了Th17细胞因子GM-CSF和IL-17F的表达。体外机制研究显示,IL-17A与其受体结合会触发Th17细胞内在自分泌环,导致转录因子NF-κB活化和IL-24诱导,从而抑制Th17细胞因子程序。体内,IL-24治疗改善了Th17诱导的EAU,而Th17细胞中IL-24沉默增强了疾病。该调节途径也在人Th17细胞中起作用。因此,IL-17A通过诱导IL-24限制Th17细胞的致病性。这些发现可以解释在葡萄膜炎中靶向IL-17A的令人失望的治疗作用。

更新日期:2020-08-18
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