HIF-2α-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis
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<sup>+</sup> 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<sup>+</sup> 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 T<sub>H</sub>1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating T<sub>H</sub>1-mediated inflammation.
Authors
- Holger K. Eltzschig (ORCID: https://orcid.org/0000-0002-5676-6473)
- Trent Clark (ORCID: https://orcid.org/0000-0002-6499-4564)
- Xiaoyi Yuan (ORCID: https://orcid.org/0000-0002-2898-6495)
- Howard Li (ORCID: https://orcid.org/0000-0002-1230-2941)
- Cristian Rodriguez‐Aguayo (ORCID: https://orcid.org/0000-0002-7880-7723)
- Xiangsheng Huang (ORCID: https://orcid.org/0000-0003-0363-2006)
- Eóin N. McNamee (ORCID: https://orcid.org/0000-0002-3331-3148)
- Gabriel Lopez‐Berestein
- Agnieszka Czopik (ORCID: https://orcid.org/0009-0000-7179-7537)
- Sandra Frank (ORCID: https://orcid.org/0000-0002-1749-0339)
- Tom Nguyen (ORCID: https://orcid.org/0000-0003-4222-4099)
- Colm B. Collins (ORCID: https://orcid.org/0000-0002-3946-1782)
- Eunyoung Tak (ORCID: https://orcid.org/0000-0002-2595-3639)
- Joanne C. Masterson (ORCID: https://orcid.org/0000-0002-8336-9879)
- Edwin F. de Zoeten (ORCID: https://orcid.org/0000-0002-0946-9759)
- Glenn T. Furuta (ORCID: https://orcid.org/0000-0003-3262-3571)
- In Hyuk Bang (ORCID: https://orcid.org/0000-0003-4666-7655)
- Wei Ruan (ORCID: https://orcid.org/0000-0002-2718-7923)
- Mark E. Gerich (ORCID: https://orcid.org/0009-0008-1952-1486)
- Yanyu Wang (ORCID: https://orcid.org/0000-0001-6915-0187)
- Anil K. Sood (ORCID: https://orcid.org/0000-0003-4242-1762)
- Victoria Vaughn
Institutions
- Ulsan College (KR)
- The University of Texas MD Anderson Cancer Center (US)
- Asan Medical Center (KR)
- LMU Klinikum (DE)
- University of Ulsan (KR)
- Children's Hospital Colorado (US)
- The University of Texas Health Science Center (US)
- University of Colorado Anschutz Medical Campus (US)
- Ludwig-Maximilians-Universität München (DE)
- The University of Texas Health Science Center at Houston (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1038/s41467-024-52113-y
- Citations
- 14
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 3.71
Funders
- U.S. Department of Defense
- Crohn's and Colitis Foundation of America
- Crohn's and Colitis Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases
- Congressionally Directed Medical Research Programs