title: Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210.
abstract: The microRNA miR-210 is a signature of hypoxia. We found robust increase in the abundance of miR-210 (>100-fold) in activated T cells, especially in the TH17 lineage of helper T cells. Hypoxia acted in synergy with stimulation via the T cell antigen receptor (TCR) and coreceptor CD28 to accelerate and increase Mir210 expression. Mir210 was directly regulated by HIF-1α, a key transcriptional regulator of TH17 polarization. Unexpectedly, we identified Hif1a as a target of miR-210, which suggested negative feedback by miR-210 in inhibiting HIF-1α expression. Deletion of Mir210 promoted TH17 differentiation under conditions of limited oxygen. In experimental colitis, miR-210 reduced the abundance of Hif1a transcripts and the proportion of cells that produced inflammatory cytokines and controlled disease severity. Our study identifies miR-210 as an important regulator of T cell differentiation in hypoxia, which can limit immunopathology.
authors.affiliation: Departments of Medicine and of Microbiology & Immunology, the Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
authors.forename: Haopeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Departments of Medicine and of Microbiology & Immunology, the Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
authors.forename: Henrik
authors.initials: H
authors.lastname: Flach
authors.affiliation: Department of Medicine University of California, San Francisco.
authors.forename: Michio
authors.initials: M
authors.lastname: Onizawa
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.affiliation: Diabetes Center, University of California, San Francisco.
authors.forename: Michael T
authors.initials: MT
authors.lastname: McManus
authors.affiliation: Departments of Medicine and of Microbiology & Immunology, the Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D015687:Cell Hypoxia / Q000276:immunology; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C549325:MIRN210 microRNA, mouse; D035683:MicroRNAs