Titel (eng)

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

Autor*in

Eric Nelius   University of Zurich

Christian Stockmann   University of Zurich

Veronika Sexl   University of Veterinary Medicine Vienna

Norihiko Takeda   Jichi Medical University

Dagmar Gotthardt   University of Veterinary Medicine Vienna

Irina Ferapontova   University of Zurich

Shunmugam Nagarajan   University of Zurich

Ewelina Krzywinska   University of Zurich

Michal Sobecki   University of Zurich

Zheng Fan   University of Zurich

Verlag

Life Science Alliance

Beschreibung (eng)

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 hypoxia-inducible transcription factors (HIFs), and the HIF-1α 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-1α 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-1α 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-1α-mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.

Sprache des Objekts

Englisch

Datum

2024

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Animals; Hypoxia-Inducible Factor 1, alpha Subunitmetabolismgenetics; Natural Cytotoxicity Triggering Receptor 1metabolismgenetics; Mice; Colitismetabolismgenetics; Fibrosis; Mice, Knockout; Lymphocytesmetabolismimmunology; Intestinal Mucosametabolismpathology; Inflammationmetabolism; Mice, Inbred C57BL; Chronic Disease; Immunity, Innate; Signal Transduction; Disease Models, Animal; Male; Intestinespathology; Antigens, Ly

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