Loss of Hypoxia inducible factor 1 in dendritic cells leads to impaired activation of protective regulatory T cells in murine colitis

Dendritic cells (DCs) play a crucial role in connecting innate and adaptive immunity and in maintaining intestinal homeostasis. DCs are highly involved in the pathogenesis of inflammatory bowel disease (IBD). IBD is associated with hypoxic inflammation where gene expression in DCs is regulated by the transcription factor hypoxia inducible factor (HIF)-1. Recent studies have described a protective role for epithelial HIF-1 in mouse models of IBD. To investigate how HIF-1α, the regulatory subunit of HIF-1, in DCs influences the development of an experimental colitis, control mice (HIF-1α^+f/+f) and knock‑out mice, which had a deficiency of dendritic HIF‑1α (CD11cCre/HIF-1α^+f/+f), were treated with 3 % dextran sodium sulfate for 7 days to induce colitis. Knock-out mice showed significantly higher weight loss at day 6 and 7 of the experiment. Colonic expressions of proinflammatory cytokines and mucin production were significantly increased in knock-out mice. Induction of regulatory T cells was impaired, and the number of forkhead box P3 regulatory T cells, which have protective effects on colitis, was diminished by dendritic HIF-1α knock-out. Our findings demonstrate that in DCs HIF-1α is necessary for the induction of sufficient numbers of regulatory T cells to control intestinal inflammation.