title: Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis.
abstract: Dendritic cells (DCs) serve as a bridge between innate and adaptive immunity and help to maintain intestinal homeostasis. Inflammatory bowel disease (IBD) is associated with dysregulation of the mucosal immune response. The concomitant hypoxic inflammation in IBD will activate the transcription factor hypoxia-inducible factor-1 (HIF-1) to also drive gene expression in DCs. Recent studies have described a protective role for epithelial HIF-1 in mouse models of IBD. We investigated the role of HIF-1 in DC function in a dextran sodium sulfate (DSS)-induced model of murine colitis. Wild-type and dendritic cell-specific HIF-1α knockout mice were treated with 3% DSS for 7 days. Knockout of HIF-1α in DCs led to a significantly larger loss of body weight in mice with DSS-induced colitis than in control mice. Knockout mice exhibited more severe intestinal inflammation with increased levels of proinflammatory cytokines and enhanced production of mucin. Induction of regulatory T cells (Tregs) was impaired, and the number of forkhead box P3 (Foxp3) Tregs was diminished by dendritic HIF-1α knockout. Our findings demonstrate that in DCs HIF-1α is necessary for the induction of sufficient numbers of Tregs to control intestinal inflammation.
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, Essen, Germany.|Physiologisches Institut, Tierärztliche Hochschule Hannover, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Flück
authors.affiliation: Physiologisches Institut, Tierärztliche Hochschule Hannover, Hannover, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Breves
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Fandrey
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Winning
mesh_terms: D000818:Animals; D001835:Body Weight; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009077:Mucins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009077:Mucins; D016264:Dextran Sulfate