Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
J Immunol. 2013 Jun 15;190(12):5972-80. doi: 10.4049/jimmunol.1300351. Epub 2013 May 17.
Th17 cells are central to the pathogenesis of autoimmune disease, and recently specific noncoding microRNAs have been shown to regulate their development. However, it remains unclear whether microRNAs 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. Using adoptive transfer experiments, we found that highly purified, myelin oligodendrocyte glycoprotein Ag-specific Th17 cells lacking miR-155 were defective in their capacity to cause experimental autoimmune encephalomyelitis. Gene expression profiling of purified miR-155(-/-)IL-17F(+) Th17 cells identified a subset of effector genes that are dependent on 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 hyporesponsive 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.
Th17 细胞是自身免疫性疾病发病机制的核心，最近已经证明特定的非编码 microRNAs 可以调节它们的发育。然而，microRNAs 是否也参与调节 Th17 细胞效应功能尚不清楚。因此，我们研究了 miR-155 在诱导实验性自身免疫性脑脊髓炎的分化 Th17 细胞中的作用。通过过继转移实验，我们发现缺乏 miR-155 的高度纯化、髓鞘少突胶质细胞糖蛋白特异性 Th17 细胞在引起实验性自身免疫性脑脊髓炎的能力上存在缺陷。对纯化的 miR-155(-/-)IL-17F(+) Th17 细胞进行基因表达谱分析，确定了一组效应基因，这些基因的适当表达依赖于 miR-155，通过一种涉及抑制转录因子 Ets1 的机制。在缺乏 miR-155 的情况下，IL-23R 减少，导致 miR-155(-/-) Th17 细胞对 IL-23 的反应性降低。综上所述，我们的研究表明 miR-155 在 Th17 细胞中释放自身免疫性炎症中起着关键作用，并发现这是通过涉及 miR-155、Ets1 和临床相关的 IL-23-IL-23R 途径的信号网络发生的。
