The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis
The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis
复制标题
DOI：
10.1093/intimm/dxv015
复制
发表时间：
2015-08-01
影响因子：
4.4
通讯作者：
Kishimoto, Tadamitsu
中科院分区：
文献类型：
--
作者：
Chinen, Ichino;Nakahama, Taisuke;Kishimoto, Tadamitsu
芳烃受体（Ahr）是一种转录因子，在肠道自身免疫性炎症中起关键作用。此外，microRNAs (miRNAs)，小的非编码寡核苷酸，介导炎症性肠病（IBD）的发病机制。然而，这些分子在IBD发病机制中的确切机制和相互作用尚未被研究。我们分析了Ahr和Ahr调控的mirna在结肠炎症中的作用。我们的研究结果表明，小鼠肠上皮细胞Ahr的缺乏加重了右旋糖酐硫酸钠诱导的结肠炎的炎症。T细胞中Ahr的缺失减轻了结肠炎，表现为抑制T- h17细胞向固有层的浸润。候选miRNA分析显示，诱导结肠炎提高了野生型小鼠结肠中miR-212/132簇的表达，而在Ahr（-/-）小鼠中，表达明显降低。此外，miR-212/132（-/-）小鼠对结肠炎具有高度抗性，T-h - 17细胞水平降低，产生il -10的CD4（+）细胞水平升高。体外分析显示，在c-Maf表达增加的miR-212/132(-/-) T细胞中，1型调节性T （Tr1）细胞的诱导显著升高。我们的研究结果强调了Ahr在肠道稳态中的重要作用，并表明抑制miR-212/132代表了治疗结肠炎的可行治疗策略。
Aryl hydrocarbon receptor (Ahr), a transcription factor, plays a critical role in autoimmune inflammation of the intestine. In addition, microRNAs (miRNAs), small non-coding oligonucleotides, mediate pathogenesis of inflammatory bowel diseases (IBD). However, the precise mechanism and interactions of these molecules in IBD pathogenesis have not yet been investigated. We analyzed the role of Ahr and Ahr-regulated miRNAs in colonic inflammation. Our results show that deficiency of Ahr in intestinal epithelial cells in mice exacerbated inflammation in dextran sodium sulfate-induced colitis. Deletion of Ahr in T cells attenuated colitis, which was manifested by suppressed T-h 17 cell infiltration into the lamina propria. Candidate miRNA analysis showed that induction of colitis elevated expression of the miR-212/132 cluster in the colon of wild-type mice, whereas in Ahr(-/-) mice, expression was clearly lower. Furthermore, miR-212/132(-/-) mice were highly resistant to colitis and had reduced levels of T-h 17 cells and elevated levels of IL-10-producing CD4(+) cells. In vitro analyses revealed that induction of type 1 regulatory T (Tr1) cells was significantly elevated in miR-212/132(-/-) T cells with increased c-Maf expression. Our findings emphasize the vital role of Ahr in intestinal homeostasis and suggest that inhibition of miR-212/132 represents a viable therapeutic strategy for treating colitis.