TY - JOUR
T1 - HIF-2α-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis
AU - Czopik, Agnieszka K.
AU - McNamee, Eóin N.
AU - Vaughn, Victoria
AU - Huang, Xiangsheng
AU - Bang, In Hyuk
AU - Clark, Trent
AU - Wang, Yanyu
AU - Ruan, Wei
AU - Nguyen, Tom
AU - Masterson, Joanne C.
AU - Tak, Eunyoung
AU - Frank, Sandra
AU - Collins, Colm B.
AU - Li, Howard
AU - Rodriguez-Aguayo, Cristian
AU - Lopez-Berestein, Gabriel
AU - Gerich, Mark E.
AU - Furuta, Glenn T.
AU - Yuan, Xiaoyi
AU - Sood, Anil K.
AU - de Zoeten, Edwin F.
AU - Eltzschig, Holger K.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-024-52113-y
DO - 10.1038/s41467-024-52113-y
M3 - Article
C2 - 39271652
AN - SCOPUS:85203981647
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 8042
ER -