在这里，研究人员报道了损伤诱导的缺氧不足以触发受损上皮细胞中的缺氧诱导因子1α (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的必要条件和充分条件。IL-17RC近端的蛋白激酶B (AKT)和ERK1/2信号通路激活哺乳动物mTOR并因此激活HIF1α。IL-17A-HIF1α驱动伤口前上皮细胞的糖酵解。IL-17RC、HIF1α的上皮特异性丢失或糖酵解的阻断会使修复脱轨。
他们的研究结果强调了炎症、代谢和迁移程序的耦合，以加快上皮细胞的愈合，并阐明了在修复过程中细胞适应缺氧压力的免疫细胞源性输入。
据了解，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生存。
附：英文原文
Title: Interleukin-17 governs hypoxic adaptation of injured epithelium
Author: Piotr Konieczny, Yue Xing, Ikjot Sidhu, Ipsita Subudhi, Kody P. Mansfield, Brandon Hsieh, Douglas E. Biancur, Samantha B. Larsen, Michael Cammer, Dongqing Li, Ning Xu Landén, Cynthia Loomis, Adriana Heguy, Anastasia N. Tikhonova, Aristotelis Tsirigos, Shruti Naik
Issue&Volume: 2022-06-16
Abstract: 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.
DOI: abg9302
Source: https://www.science.org/doi/10.1126/science.abg9302