Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling.
Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling.
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DOI：
10.1371/journal.pone.0056595
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yamamura T
中科院分区：
文献类型：
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作者：
Raveney BJ;Oki S;Yamamura T
产生IL-17的CD 4 + T辅助17（Th 17）细胞在一系列人类自身免疫性疾病和相应的动物模型中是致病性的。我们现在证明，这种T细胞浸润的靶器官在诱导实验性自身免疫性脑脊髓炎（EAE）和实验性自身免疫性葡萄膜视网膜炎（EAU）特异性表达NR 4A 2。此外，我们揭示了NR 4A 2在Th 17细胞功能和Th 17细胞驱动的自身免疫性疾病中的重要参与。当用siRNA阻断NR 4A 2表达时，体外完全Th 17分化被阻止：尽管细胞表达主要Th 17调节因子RORγt，但它们表达降低水平的IL-23 R，并且不能产生IL-17和IL-21。值得注意的是，外源性IL-21恢复了不存在NR 4A 2的Th 17分化，表明NR 4A 2通过自分泌IL-21信号传导控制Th 17细胞的完全成熟。通过用NR 4A 2特异性siRNA全身性治疗来防止体内NR 4A 2表达也降低了Th 17效应子应答，并且进一步保护小鼠免于EAE诱导。此外，缺乏疾病与自分泌IL-21产生和IL-23 R表达的减少有关。NR 4A 2表达的类似调节作为干预也是有效的，逆转了已建立的自身免疫应答并改善了临床疾病症状。因此，NR 4A 2似乎控制Th 17分化，因此在Th 17介导的自身免疫性疾病的发展中起重要作用。由于NR 4A 2在人类自身免疫性疾病期间也上调，因此靶向NR 4A 2可能为治疗自身免疫性疾病提供新的治疗方法。
IL-17-producing CD4+ T helper 17 (Th17) cells are pathogenic in a range of human autoimmune diseases and corresponding animal models. We now demonstrate that such T cells infiltrating the target organ during the induction of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveoretinitis (EAU) specifically express NR4A2. Further, we reveal a critical involvement of NR4A2 in Th17 cell functions and Th17 cell-driven autoimmune diseases. When NR4A2 expression was blocked with siRNA, full Th17 differentiation was prevented in vitro: although cells expressed the master Th17 regulator, RORγt, they expressed reduced levels of IL-23R and were unable to produce IL-17 and IL-21. Notably, Th17 differentiation in the absence of NR4A2 was restored by exogenous IL-21, indicating that NR4A2 controls full maturation of Th17 cells via autocrine IL-21 signalling. Preventing NR4A2 expression in vivo by systemic treatment with NR4A2-specific siRNA also reduced Th17 effector responses and furthermore protected mice from EAE induction. In addition, the lack of disease was associated with a reduction in autocrine IL-21 production and IL-23R expression. Similar modulation of NR4A2 expression was also effective as an intervention, reversing established autoimmune responses and ameliorating clinical disease symptoms. Thus, NR4A2 appears to control Th17 differentiation and so plays an essential role in the development of Th17-mediated autoimmune disease. As NR4A2 is also upregulated during human autoimmune disease, targeting NR4A2 may provide a new therapeutic approach in treating autoimmune disease.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
4.3
作者：
Hofstetter, HH;Ibrahim, SM;Gold, R
通讯作者：
Gold, R
影响因子：
30.8
作者：
Le, WD;Xu, PY;Vassilatis, DK
通讯作者：
Vassilatis, DK
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影响因子：
15.3
作者：
Das, Jyoti;Ren, Guangwen;Zhang, Liying;Roberts, Arthur I.;Zhao, Xin;Bothwell, Alfred L. M.;Van Kaer, Luc;Shi, Yufang;Das, Gobardhan
通讯作者：
Das, Gobardhan
影响因子：
30.5
作者：
通讯作者：
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