Czopik AK, McNamee EN, Vaughn V, Huang X, Bang IH, Clark T, Wang Y, Ruan W, Nguyen T, Masterson JC, Tak E, Frank S, Collins CB, Li H, Rodriguez-Aguayo C, Lopez-Berestein G, Gerich ME, Furuta GT, Yuan X, Sood AK, de Zoeten EF, Eltzschig HK: HIF-2alpha-dependent induction of miR-29a restrains T(H)1 activity during T cell dependent colitis. Nat Commun 2024; 15: 8042- Outcomes Research Consortium

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Czopik AK, McNamee EN, Vaughn V, Huang X, Bang IH, Clark T, Wang Y, Ruan W, Nguyen T, Masterson JC, Tak E, Frank S, Collins CB, Li H, Rodriguez-Aguayo C, Lopez-Berestein G, Gerich ME, Furuta GT, Yuan X, Sood AK, de Zoeten EF, Eltzschig HK: HIF-2alpha-dependent induction of miR-29a restrains T(H)1 activity during T cell dependent colitis. Nat Commun 2024; 15: 8042

May 14, 2024

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-2alpha in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2alpha 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-2alpha or delivery of miR-29a mimetic dampen T(H)1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating T(H)1-mediated inflammation