Departments of Medicine and of Microbiology & Immunology, the Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
Department of Medicine University of California, San Francisco.
Nat Immunol. 2014 Apr;15(4):393-401. doi: 10.1038/ni.2846. Epub 2014 Mar 9.
The microRNA miR-210 is a signature of hypoxia. We found robust increase in the abundance of miR-210 (>100-fold) in activated T cells, especially in the TH17 lineage of helper T cells. Hypoxia acted in synergy with stimulation via the T cell antigen receptor (TCR) and coreceptor CD28 to accelerate and increase Mir210 expression. Mir210 was directly regulated by HIF-1α, a key transcriptional regulator of TH17 polarization. Unexpectedly, we identified Hif1a as a target of miR-210, which suggested negative feedback by miR-210 in inhibiting HIF-1α expression. Deletion of Mir210 promoted TH17 differentiation under conditions of limited oxygen. In experimental colitis, miR-210 reduced the abundance of Hif1a transcripts and the proportion of cells that produced inflammatory cytokines and controlled disease severity. Our study identifies miR-210 as an important regulator of T cell differentiation in hypoxia, which can limit immunopathology.
miR-210 是一种低氧特征性的 microRNA。我们发现，在活化的 T 细胞中，miR-210 的丰度显著增加（>100 倍），尤其是在辅助性 T 细胞的 TH17 谱系中。缺氧与 T 细胞抗原受体（TCR）和共受体 CD28 的刺激协同作用，加速并增加 Mir210 的表达。Mir210 直接受到 HIF-1α的调控，HIF-1α 是 TH17 极化的关键转录调节因子。出人意料的是，我们发现 Hif1a 是 miR-210 的靶标，这表明 miR-210 通过负反馈抑制 HIF-1α的表达。在有限氧的条件下，Mir210 的缺失促进了 TH17 的分化。在实验性结肠炎中，miR-210 减少了 Hif1a 转录本的丰度以及产生炎症细胞因子的细胞比例，并控制了疾病的严重程度。我们的研究表明，miR-210 是低氧条件下 T 细胞分化的一个重要调节因子，它可以限制免疫病理学。
