Expression of the transcription factor HIF-1a in NKp46+ innate lymphoid cells limits inflammation and fibrosis upon chronic colitis
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-1a 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-1a 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-1a 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 a mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage. Overall design: In order to assess the impact of HIF1a-deficiency in NKp46+ cells on the gut microenvironment beyond the immune cell compartment at the whole tissue level and at single-cell resolution, we performed single nuclei RNA sequencing on frozen colon tissue from WT and HIF1a KO mice after chronic DSS exposure.