RT Journal Article
SR Electronic
T1 The transcription factor HIF-1α in NKp46+ ILCs limits chronic intestinal inflammation and fibrosis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202402593
DO 10.26508/lsa.202402593
VO 7
IS 9
A1 Nelius, Eric
A1 Fan, Zheng
A1 Sobecki, Michal
A1 Krzywinska, Ewelina
A1 Nagarajan, Shunmugam
A1 Ferapontova, Irina
A1 Gotthardt, Dagmar
A1 Takeda, Norihiko
A1 Sexl, Veronika
A1 Stockmann, Christian
YR 2024
UL http://www.life-science-alliance.org/content/7/9/e202402593.abstract
AB 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.The single-nucleus RNA-seq data of mouse colon reported in this study are deposited at the Gene Expression Omnibus (GEO) repository under the accession number GSE252602. All data are available in the main text or the supplementary materials, and raw data files that support the findings of this study are available from the corresponding author upon reasonable request.