MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis
MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis
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DOI：
10.1172/jci74347
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发表时间：
2015-03-01
影响因子：
15.9
通讯作者：
Weiner, Howard L.
中科院分区：
文献类型：
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作者：
Murugaiyan, Gopal;da Cunha, Andre Pires;Weiner, Howard L.
产生IL-17的Th17细胞的积累与多种自身免疫性疾病的发生有关；然而，microRNA （miRNA）途径对Th17发育的内在控制的贡献尚不清楚。在这里，我们证明了miR-21在Th17细胞中的表达升高，缺乏miR-21的小鼠在Th17分化中存在缺陷，并且对实验性自身免疫性脑脊髓炎（EAE）具有抗性。此外，我们确定miR-21通过靶向和消耗tgf - β信号的负调节因子SMAD-7来促进Th17分化。此外，miR-21缺陷T细胞中Th17分化的减少与SMAD-2/3激活和IL-2抑制的缺陷有关。最后，我们发现用抗miR-21寡核苷酸治疗WT小鼠降低了EAE的临床严重程度，这与Th17细胞的减少有关。因此，我们表征了T细胞内在的miRNA通路，该通路增强tgf - β信号，限制IL-2的自分泌抑制作用，从而促进Th17分化和自身免疫。
Accumulation of IL-17 producing Th17 cells is associated with the development of multiple autoimmune diseases; however, the contribution of microRNA (miRNA) pathways to the intrinsic control of Th17 development remains unclear. Here, we demonstrated that miR-21 expression is elevated in Th17 cells and that mice lacking miR-21 have a defect in Th17 differentiation and are resistant to experimental autoimmune encephalomyelitis (EAE). Furthermore, we determined that miR-21 promotes Th17 differentiation by targeting and depleting SMAD-7, a negative regulator of TGF-beta signaling. Moreover, the decreases in Th17 differentiation in miR-21 deficient T cells were associated with defects in SMAD-2/3 activation and IL-2 suppression. Finally, we found that treatment of WT mice with an anti miR-21 oligonucleotide reduced the clinical severity of EAE, which was associated with a decrease in Th17 cells. Thus, we have characterized a T cell intrinsic miRNA pathway that enhances TGF-beta signaling, limits the autocrine inhibitory effects of IL-2, and thereby promotes Th17 differentiation and autoimmunity.