Hif-2α-Dependent Induction of miR-29a Restrains TH1 Activity During T Cell Dependent Colitis

Authors

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 de Zoeten
Holger K Eltzschig

Publication Date

9-14-2024

Journal

Nature Communications

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.

Keywords

Animals, MicroRNAs, Basic Helix-Loop-Helix Transcription Factors, Colitis, Th1 Cells, Mice, Mice, Inbred C57BL, T-Box Domain Proteins, CD4-Positive T-Lymphocytes, Mice, Knockout, Humans, Female, Disease Models, Animal, Male, Lymphocyte activation, Acute inflammation, Inflammatory bowel disease, CD4-positive T cells

Comments

Supplementary Materials

Data Availability Statement

PMID: 39271652