The transcription factor HIF-1α in NKp46+ ILCs limits chronic intestinal inflammation and fibrosis

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Gotthardt-Pötsch, Dagmar

Abstrakt

Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to low oxygen is mediated by hypoxiainducible transcription factors (HIFs), and the HIF-1 alpha subunit shapes an ILC phenotype upon acute colitis that contributes to intestinal damage. However, the impact of HIF signaling in NKp46+ ILCs in the context of repetitive mucosal damage and chronic inflammation, as it typically occurs during inflammatory bowel disease, is unknown. In chronic colitis, mice lacking the HIF-1 alpha isoform in NKp46+ ILCs show a decrease in NKp46+ ILC1s but a concomitant rise in neutrophils and Ly6Chigh macrophages. Single-nucleus RNA sequencing suggests enhanced interaction of mesenchymal cells with other cell compartments in the colon of HIF-1 alpha KO mice and a loss of mucus-producing enterocytes and intestinal stem cells. This was, furthermore, associated with increased bone morphogenetic pathway-integrin signaling, expansion of fibroblast subsets, and intestinal fibrosis. In summary, this suggests that HIF-1 alpha-mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.

Dokumententyp

Originalarbeit

Open Access Type

Gold

WoS ID

WOS:001248535800002

Repository Phaidra

o:3179