HIF-2α-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis
Agnieszka Czopik, Eóin N. McNamee, Victoria Vaughn, Xiangsheng Huang, In Hyuk Bang, Trent Clark, Yanyu Wang, Wei Ruan, Tom Nguyen, Joanne C. Masterson, Eunyoung Tak, Sandra Frank, Colm B. Collins, Howard Li, Cristian Rodriguez‐Aguayo, Gabriel Lopez‐Berestein, Mark E. Gerich, Glenn T. Furuta, Xiaoyi Yuan, Anil K. Sood, Edwin F. de Zoeten, Holger K. Eltzschig
Abstract
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 TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation. Inflammatory intestinal lesions are often hypoxic, which results in the stabilization and activation of hypoxia-inducible-factors (HIF). Here authors show that in a mouse model of colitis, HIF-2α is specifically stabilized in CD4+ type 1T helper (TH1) cells, leading to the upregulation of miR-29a expression and suppression of TH1 cell function, which pathway is potentially targetable for therapeutic purposes.