The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression.
The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression.
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DOI：
10.1016/j.immuni.2016.05.015
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发表时间：
2016-06-21
期刊：
影响因子：
32.4
通讯作者：
Dong C
中科院分区：
文献类型：
--
作者：
Ichiyama K;Gonzalez-Martin A;Kim BS;Jin HY;Jin W;Xu W;Sabouri-Ghomi M;Xu S;Zheng P;Xiao C;Dong C
T辅助17 （Th17）细胞在自身免疫性疾病中起着关键作用。然而，非编码rna在Th17细胞发育和功能中的作用在很大程度上是未知的。我们发现在Th17细胞中特异性地缺失核糖核酸内切酶Dicer1基因可以保护小鼠免受实验性自身免疫性脑脊髓炎。我们发现dicer1调控的microRNA (miR)-183-96-182簇（miR- 183c）在Th17细胞中高表达，并受细胞因子IL-6-STAT3信号诱导。miR-183C表达增强Th17细胞在发育过程中致病细胞因子的产生，促进自身免疫。在机制上，Th17细胞中的miR-183C直接抑制转录因子Foxo1的表达。Foxo1部分通过抑制细胞因子受体IL-1R1的表达负向调控Th17细胞的致病性。这些发现表明，miR-183C通过抑制Foxo1来驱动自身免疫性疾病中Th17的致病性，并提供了有希望的治疗靶点。表观遗传调控是T细胞分化的重要调控机制。然而，mirna在Th17细胞发育和功能中的作用尚不清楚。Dong等发现miR-183C是Th17细胞特异性致病性miRNA，并证明miR-183C通过抑制Foxo1表达促进Th17细胞致病性。
T helper 17 (Th17) cells are key players in autoimmune diseases. However, the roles of non-coding RNAs in Th17 cell development and function are largely unknown. We found that deletion of the endoribonuclease Dicer1 gene specifically in Th17 cells protected mice from experimental autoimmune encephalomyelitis. We found that the Dicer1-regulated microRNA (miR)-183-96-182 cluster (miR-183C) was highly expressed in Th17 cells and was induced by cytokine IL-6-STAT3 signaling. miR-183C expression enhanced pathogenic cytokine production from Th17 cells during their development and promoted autoimmunity. Mechanistically, miR-183C in Th17 cells directly repressed expression of the transcription factor Foxo1. Foxo1 negatively regulated the pathogenicity of Th17 cells in part by inhibiting cytokine receptor IL-1R1 expression. These findings indicate that the miR-183C drives Th17 pathogenicity in autoimmune diseases via inhibition of Foxo1 and present promising therapeutic targets. Epigenetic regulation is important for T cell differentiation. However, the roles of miRNAs in Th17 cell development and function are unclear. Dong and colleagues identify miR-183C as a pathogenic Th17 cell-specific miRNA and demonstrate that miR-183C promotes Th17 cell pathogenicity via suppression of Foxo1 expression.