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Expression of the transcription factor HIF-1α in NKp46+ innate lymphoid cells limits inflammation and fibrosis upon chronic colitis

ABSTRACT: Innate lymphoid cells (ILCs) are critically involved in intestinal adaptation to microenvironmental challenges (Colonna, 2018; Guendel et al., 2020) and the gut mucosa is characterized by low oxygen. Adaptation to low oxygen is mediated by Hypoxia-inducible transcription factors (HIFs) the HIF-1α subunit shapes the ILC phenotype upon acute experimental colitis and contributes to intestinal damage. However, the impact of HIF signaling in NKp46+ ILC in the context of repetitive mucosal damage and chronic inflammation, as it typically occurs during inflammatory bowel disease, is unknown. In a model of chronic colitis, mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in NKp46+ ILC1s but a concomitant rise in neutrophils as well as Ly6C high macrophages. Single-nuclei RNA sequencing suggests enhanced interaction of mesenchymal cells with other cell compartments in the colon of HIF-1α KO mice and a loss of mucus-producing enterocytes as well as intestinal stem cells. This was, furthermore, associated with increased BMP-integrin signaling, expansion of profibrotic fibroblasts subsets and intestinal fibrosis. In summary this suggests that HIF-1 α mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.

ORGANISM(S): Mus musculus

PROVIDER: GSE252602 | GEO | 2024/06/12

REPOSITORIES: GEO

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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).

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Expression of the transcription factor HIF-1α in NKp46+ innate lymphoid cells limits inflammation and fibrosis upon chronic colitis

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