Interleukin-17 governs hypoxic adaptation of injured epithelium

Science. 2022 Jul 8;377(6602):eabg9302. doi: 10.1126/science.abg9302. Epub 2022 Jul 8.

Abstract

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 HIF1α in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that retinoic acid-related orphan receptor γt+ (RORγt+) γδ T cell-derived interleukin-17A (IL-17A) is necessary and sufficient to activate HIF1α. 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 HIF1α. The IL-17A-HIF1α axis drives glycolysis in wound front epithelia. Epithelial-specific loss of IL-17RC, HIF1α, 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.

MeSH terms

  • Animals
  • Epithelium / injuries
  • Epithelium / metabolism
  • Gene Expression Profiling
  • Humans
  • Hypoxia* / immunology
  • Hypoxia* / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit* / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Interleukin-17* / metabolism
  • Mice
  • Receptors, Interleukin-17*
  • Signal Transduction
  • Single-Cell Analysis
  • T-Lymphocytes / immunology
  • Wound Healing* / immunology

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-17
  • Receptors, Interleukin-17