24自分泌诱导产生的负反馈回路限制Th17致病性

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本期文章:《免疫》:Online/在线发表

近日,美国国立卫生研究院Rachel R. Caspi及其研究小组的工作显示,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致病性。这一研究成果发表于2020年7月15日在线发表在《免疫》上。

研究人员发现,Th17细胞受其自身的特征性细胞因子IL-17A调控。自体致病性Th17细胞中IL-17A的丧失并没有降低其致病性,反而提高了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,从而激活转录因子NF-κB并诱导IL-24,进而抑制Th17细胞因子程序。

 

在体内,IL-24治疗可改善Th17诱导的EAU,而Th17细胞中IL-24的沉默可增强疾病。该调节途径也在人类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的失败结果。

 

据了解,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,靶向葡萄膜炎IL-17A的临床试验并不成功。

 

附:英文原文

Title: The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24

Author: Wai Po Chong, Mary J. Mattapallil, Kumarkrishna Raychaudhuri, So Jin Bing, Sihan Wu, Yajie Zhong, WeiWei Wang, Zilin Chen, Phyllis B. Silver, Yingyos Jittayasothorn, Chi-Chao Chan, Jun Chen, Reiko Horai, Rachel R. Caspi

Issue&Volume: 2020-07-15

Abstract: 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.

DOI: 10.1016/j.immuni.2020.06.022

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30277-6

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