HIF-2α-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis

Agnieszka K. 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. Zoeten () and Holger K. Eltzschig
Additional contact information
Agnieszka K. Czopik: The University of Texas Health Science Center at Houston
Eóin N. McNamee: University of Colorado Anschutz School of Medicine
Victoria Vaughn: The University of Texas Health Science Center at Houston
Xiangsheng Huang: The University of Texas Health Science Center at Houston
In Hyuk Bang: The University of Texas Health Science Center at Houston
Trent Clark: The University of Texas Health Science Center at Houston
Yanyu Wang: The University of Texas Health Science Center at Houston
Wei Ruan: The University of Texas Health Science Center at Houston
Tom Nguyen: University of Colorado Anschutz School of Medicine
Joanne C. Masterson: University of Colorado Anschutz School of Medicine
Eunyoung Tak: Children’s Hospital Colorado
Sandra Frank: University of Colorado - Anschutz Medical Campus
Colm B. Collins: University of Colorado Anschutz School of Medicine
Howard Li: University of Colorado - Anschutz Medical Campus
Cristian Rodriguez-Aguayo: The University of Texas MD Anderson Cancer Center
Gabriel Lopez-Berestein: The University of Texas MD Anderson Cancer Center
Mark E. Gerich: University of Colorado Anschutz School of Medicine
Glenn T. Furuta: University of Colorado Anschutz School of Medicine
Xiaoyi Yuan: The University of Texas Health Science Center at Houston
Anil K. Sood: The University of Texas MD Anderson Cancer Center
Edwin F. Zoeten: University of Colorado Anschutz School of Medicine
Holger K. Eltzschig: The University of Texas Health Science Center at Houston

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52113-y

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