Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA.
Nat Commun. 2024 Sep 14;15(1):8042. doi: 10.1038/s41467-024-52113-y.
Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4 T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4 T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen T1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating T1-mediated inflammation.
代谢失衡导致炎症性缺氧和缺氧诱导转录因子 (HIFs) 的稳定是炎症性肠病的标志。我们假设 HIF 可在肠道炎症期间在 CD4 T 细胞中稳定，并通过调节 microRNAs 改变 T 细胞的功能反应。我们的检测结果显示，在实验性结肠炎期间，T 细胞内在的缺氧和 HIF 蛋白的稳定明显增加。在原代 CD4 T 细胞中的 microRNA 筛选使我们发现了 miR-29a，并进一步研究确定了 HIF-2α 在 CD4 细胞内在诱导缺氧时 miR-29a 的选择性作用。在 T 细胞中具有内在 HIF-2α 缺失的小鼠表现出升高的 T 细胞因子（miR-29a 的靶标）水平和加重的肠道炎症。在 T 细胞中具有 miR-29a 缺乏的小鼠表现出增强的肠道炎症。T 细胞内在过表达 HIF-2α 或递送 miR-29a 模拟物可减轻 T1 驱动的结肠炎。在这项工作中，我们展示了以前未被认识到的缺氧依赖性诱导 miR-29a 在减轻 T1 介导的炎症中的作用。
