Interleukin-17 governs hypoxic adaptation of injured epithelium

Mammalian cells autonomously activate hypoxia-inducible transcription factors (HIFs) to ensure survival in low-oxygen environments. We report here that injury-induced hypoxia is insufficient to trigger HIF1 alpha in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that retinoic acid-related orphan receptor gamma t(+) (ROR gamma t(+)) gamma delta T cell-derived interleukin-17A (IL-17A) is necessary and sufficient to activate HIF1 alpha. Protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling proximal of IL-17 receptor C (IL-17RC) activates mammalian target of rapamycin (mTOR) and consequently HIF1 alpha. The IL-17A-HIF1 alpha axis drives glycolysis in wound front epithelia. Epithelial-specific loss of IL-17RC, HIF1 alpha, or blockade of glycolysis derails repair. Our findings underscore the coupling of inflammatory, metabolic, and migratory programs to expedite epithelial healing and illuminate the immune cell-derived inputs in cellular adaptation to hypoxic stress during repair.

Automated summary

Mammalian cells activate HIFs to survive in low-oxygen environments, but injury-induced hypoxia is unable to activate HIF1 alpha. However, IL-17A derived from ROR gamma t(+) gamma delta T cells can activate HIF1 alpha. The IL-17A-HIF1 alpha axis promotes glycolysis for wound healing in epithelial cells, and loss of IL-17RC, HIF1 alpha, or blockade of glycolysis disrupts the repair process. These findings highlight the interconnectedness of inflammation, metabolism, and migration programs, as well as the role of immune cell-derived inputs in cellular adaptation to hypoxic stress during repair.