Hypoxia enhances ILC3 responses through HIF-1α-dependent mechanism

J. L. Fachi, L. P. Pral, J. A.C. dos Santos, A. C. Codo, S. de Oliveira, J. S. Felipe, F. F.F. Zambom, N. O.S. Câmara, P. M.M.M. Vieira, M. Colonna, M. A.R. Vinolo

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa homeostasis. The hypoxia-inducible factor (HIF) is an important modulator of immune cell activation and a key mechanism for cellular adaptation to oxygen deprivation. However, its role on ILC3 is not well known. In this study, we investigated how a hypoxic environment modulates ILC3 response and the subsequent participation of HIF-1 signaling in this process. We found increased proliferation and activation of intestinal ILC3 at low oxygen levels, a response that was phenocopied when HIF-1α was chemically stabilized and was reversed when HIF-1 was blocked. The increased activation of ILC3 relied on a HIF-1α-dependent transcriptional program, but not on mTOR-signaling or a switch to glycolysis. HIF-1α deficiency in RORyt compartment resulted in impaired IL-17 and IL-22 production by ILC3 in vivo, which reflected in a lower expression of their target genes in the intestinal epithelium and an increased susceptibility to Clostridiodes difficile infection. Taken together, our results show that HIF-1α activation in intestinal ILC3 is relevant for their functions in steady state and infectious conditions.

Original languageEnglish
Pages (from-to)828-841
Number of pages14
JournalMucosal Immunology
Volume14
Issue number4
DOIs
StatePublished - Jul 2021

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