MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression.
MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression.
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DOI：
10.4049/jimmunol.1300351
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发表时间：
2013-06-15
期刊：
影响因子：
--
通讯作者：
O'Connell RM
中科院分区：
文献类型：
--
作者：
Hu R;Huffaker TB;Kagele DA;Runtsch MC;Bake E;Chaudhuri AA;Round JL;O'Connell RM
Th 17细胞在自身免疫性疾病的发病机制中起着重要作用，最近发现特异性非编码microRNAs（miRNAs）可调控Th 17细胞的发育。然而，目前还不清楚miRNAs是否也参与调节Th 17细胞效应子功能。因此，我们研究了miR-155在诱导实验性自身免疫性脑脊髓炎（EAE）过程中分化的Th 17细胞中的作用。使用过继转移实验，我们发现，高度纯化，MOG抗原特异性Th 17细胞缺乏miR-155的能力，导致EAE的缺陷。纯化的miR-155−/− IL-17 F + Th 17细胞的基因表达谱鉴定了一个效应基因亚组，其通过涉及转录因子Ets 1抑制的机制依赖于miR-155进行适当表达。在缺乏miR-155的情况下，IL-23 R基因减少，导致miR-155−/− Th 17细胞对IL-23低应答。综上所述，我们的研究证明了miR-155在Th 17细胞释放自身免疫性炎症时的关键作用，并发现这是通过涉及miR-155，Ets 1和临床相关IL-23-IL-23 R通路的信号网络发生的。
Th17 cells are central to the pathogenesis of autoimmune disease, and recently specific noncoding microRNAs (miRNAs) have been shown to regulate their development. However, it remains unclear if miRNAs are also involved in modulating Th17 cell effector functions. Consequently, we examined the role of miR-155 in differentiated Th17 cells during their induction of Experimental Autoimmune Encephalomyelitis (EAE). Using adoptive transfer experiments, we found that highly purified, MOG antigen-specific Th17 cells lacking miR-155 were defective in their capacity to cause EAE. Gene expression profiling of purified miR-155−/− IL-17F+ Th17 cells identified a subset of effector genes that are dependent upon miR-155 for their proper expression through a mechanism involving repression of the transcription factor Ets1. Among the genes reduced in the absence of miR-155 was IL-23R, resulting in miR-155−/− Th17 cells being hypo-responsive to IL-23. Taken together, our study demonstrates a critical role for miR-155 in Th17 cells as they unleash autoimmune inflammation, and finds that this occurs through a signaling network involving miR-155, Ets1 and the clinically relevant IL-23-IL-23R pathway.
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