University of Zurich, Institute of Anatomy, Zurich, Switzerland.
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, Marseille, France.
Nat Commun. 2021 Aug 4;12(1):4700. doi: 10.1038/s41467-021-25065-w.
During skin injury, immune response and repair mechanisms have to be coordinated for rapid skin regeneration and the prevention of microbial infections. Natural Killer (NK) cells infiltrate hypoxic skin lesions and Hypoxia-inducible transcription factors (HIFs) mediate adaptation to low oxygen. We demonstrate that mice lacking the Hypoxia-inducible factor (HIF)-1α isoform in NK cells show impaired release of the cytokines Interferon (IFN)-γ and Granulocyte Macrophage - Colony Stimulating Factor (GM-CSF) as part of a blunted immune response. This accelerates skin angiogenesis and wound healing. Despite rapid wound closure, bactericidal activity and the ability to restrict systemic bacterial infection are impaired. Conversely, forced activation of the HIF pathway supports cytokine release and NK cell-mediated antibacterial defence including direct killing of bacteria by NK cells despite delayed wound closure. Our results identify, HIF-1α in NK cells as a nexus that balances antimicrobial defence versus global repair in the skin.
在皮肤损伤时，免疫反应和修复机制必须协调一致，以实现快速的皮肤再生和防止微生物感染。自然杀伤 (NK) 细胞浸润缺氧性皮肤损伤，缺氧诱导转录因子 (HIF) 介导对低氧的适应。我们证明，缺乏 NK 细胞中缺氧诱导因子 (HIF)-1α 同工型的小鼠表现出细胞因子干扰素 (IFN)-γ 和粒细胞巨噬细胞集落刺激因子 (GM-CSF) 释放受损，这是免疫反应减弱的一部分。这加速了皮肤血管生成和伤口愈合。尽管伤口迅速闭合，但杀菌活性和限制全身细菌感染的能力受损。相反，强制激活 HIF 通路支持细胞因子释放和 NK 细胞介导的抗菌防御，包括 NK 细胞对细菌的直接杀伤，尽管伤口闭合延迟。我们的研究结果确定，NK 细胞中的 HIF-1α 作为一个枢纽，平衡了皮肤中的抗菌防御与全局修复。
