Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210

H Wang, H Flach, M Onizawa, L Wei, MT McManus… - Nature …, 2014 - nature.com
H Wang, H Flach, M Onizawa, L Wei, MT McManus, A Weiss
Nature immunology, 2014nature.com
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 …
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.
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