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

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.

The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut

“…Likewise, as reported by Fachi et al (2021) in RORγt-expressing ILC3s, HIF1α binds to the Rorc promoter but not the Tbx21 promoter and supports IL-22 and IL-17 expression (Fachi et al, 2021). In contrast to the investigation by Fachi et al (2021) that analyzed cytokine expression and HIF1α binding to the Rorc promoter by ChIP in the ILC3 cell line MNK3 after short-term exposure (up to 3 h) to near-anoxic conditions, we assessed Rorc and Tbx21 expression after 20 h of exposure to IL-12 and HIF1α binding to the Tbx21 promoter after 8-h incubation with IL-12 by Cut & Run in primary murine WT and HIF1α KO NKp46 + cells. Therefore, in addition to the different in vitro cell systems, the different stimuli and the duration of stimulation are likely to contribute to the observed discrepancies.…”

“…HIF-1α was also implicated in fostering the development of Th17 cells through direct transcriptional activation of RORγt (Dang et al, 2011). Likewise, as reported by Fachi et al (2021) in RORγt-expressing ILC3s, HIF1α binds to the Rorc promoter but not the Tbx21 promoter and supports IL-22 and IL-17 expression (Fachi et al, 2021). In contrast to the investigation by Fachi et al (2021) that analyzed cytokine expression and HIF1α binding to the Rorc promoter by ChIP in the ILC3 cell line MNK3 after short-term exposure (up to 3 h) to near-anoxic conditions, we assessed Rorc and Tbx21 expression after 20 h of exposure to IL-12 and HIF1α binding to the Tbx21 promoter after 8-h incubation with IL-12 by Cut & Run in primary murine WT and HIF1α KO NKp46 + cells.…”

Role of Innate lymphoid Cells in Obesity and Insulin Resistance

“…mTOR signaling influences ILC3s in the intestine, leading to subsequent alteration in metabolic homeostasis. Notably, another study has reported that activation of ILC3s upon low oxygen challenge occurs via a HIF-1α-dependent mechanism instead of mTOR-signaling ( 146 ). P38 MAPK pathway also regulates the production of GM-CSF by ILC3s after activation of death receptor 3 (DR3) signaling ( 147 , 148 ).…”

Heartbreakers or Healers? Innate Lymphoid Cells in Cardiovascular Disease and Obesity

“…Although in that study, no effect of ox-LDL stimulation on ILC3s was observed, suggestive of other disease-specific effects of ox-LDL signalling on ILCs. ILC3s are regulated by hypoxia, acting via hypoxia inducible factor (HIF)-1α ( 78 ). Tissue hypoxia can be induced by, and contribute to CVDs ( 79 ).…”