Mammalian cells autonomously activate hypoxia-inducible transcription factors to ensure survival in low-oxygen environments. We report that injury-induced hypoxia is insufficient to trigger hypoxia-inducible factor 1 alpha (HIF1α) in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that RORγt + γδ T cell–derived interleukin (IL)-17A, is necessary and sufficient to activate HIF1α. Protein kinase B (AKT) and ERK1/2 signaling proximal of IL-17RC activates mammalian target of rapamycin (mTOR) and consequently HIF1α. The IL-17A–HIF1α 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.

中文翻译：

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白细胞介素 17 控制受损上皮的缺氧适应

哺乳动物细胞自主激活缺氧诱导转录因子，以确保在低氧环境中存活。我们报告说，损伤引起的缺氧不足以触发受损上皮细胞中的缺氧诱导因子 1 α (HIF1α)。相反，多模式单细胞和空间转录组学分析和功能研究表明 RORγt+γδ T 细胞衍生的白细胞介素 (IL)-17A 是激活 HIF1α 所必需且充分的。IL-17RC 近端的蛋白激酶 B (AKT) 和 ERK1/2 信号激活哺乳动物雷帕霉素靶标 (mTOR)，从而激活 HIF1α。IL-17A–HIF1α 驱动伤口前上皮细胞的糖酵解。上皮特异性 IL-17RC、HIF1α 缺失或糖酵解阻断会破坏修复。我们的研究结果强调了炎症、代谢和迁移程序的耦合，以加速上皮愈合并阐明免疫细胞衍生的输入在修复过程中细胞适应缺氧应激。