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.

A Correction to this paper has been published: https://doi.org/10.1038/s41385-021-00403-9.

Insulin resistance is a common feature in diabetic population. One target that has been given some attention is the transcriptional factor hypoxia inducible factor (HIF‐1α). Our proposal was to evaluate the role of HIF‐1α in insulin resistant skeletal muscle cells (Ethics protocol no. 063/2012 FMRP‐USP). After differentiation, the cells were exposed to different nutrients: glucose, palmitic acid 600 µM and AICAR (500 µM). The oxygen consumption was measured using a Clark‐type electrode (Hansatech Instruments). Analyses of western blotting were performed for proteins quantifying HIF‐1α. In addition, the mRNA level of HIF‐1α and β‐actin was determined by qPCR‐Realtime. The oxygen consumption was significantly increased in the presence of AICAR in compared to control (p<0.05). The mRNA levels HIF‐1α showed an increased expression when compared to the mRNA levels HIF‐2α in muscle cells (p<0.05). The mRNA levels of HIF‐1α showed a significant increase in AICAR compared to control and palmitic acid treated cells (p<0.05). In addition, AICAR treatment increased HIF‐1α gene expression (p<0.05). The elevated HIF‐1α was associated with reduced reactive oxygen species (ROS) production and elevated insulin response as indicated by Akt phosphorylated levels. These results, therefore, suggest that under elevated expression of HIF‐1α is an important mechanism to protect the cells against insulin resistance and mitochondrial dysfunction.Financial Support: FAPESP Process number: 2012/17416‐2 ‐ Corn Products of Brazil.