NK cells in hypoxic skin mediate a trade-off between wound healing and antibacterial defence

Michal Sobecki, Ewelina Krzywinska, Shunmugam Nagarajan, Annette Audigé, Khanh Huỳnh, Julian Zacharjasz, Julien Debbache, Yann Kerdiles, Dagmar Gotthardt, Norihiko Takeda, Joachim Fandrey, Lukas Sommer, Veronika Sexl and Christian Stockmann ()
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Michal Sobecki: University of Zurich, Institute of Anatomy
Ewelina Krzywinska: University of Zurich, Institute of Anatomy
Shunmugam Nagarajan: University of Zurich, Institute of Anatomy
Annette Audigé: University of Zurich, Institute of Anatomy
Khanh Huỳnh: University of Zurich, Institute of Anatomy
Julian Zacharjasz: University of Zurich, Institute of Anatomy
Julien Debbache: University of Zurich, Institute of Anatomy
Yann Kerdiles: Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280
Dagmar Gotthardt: University of Veterinary Medicine
Norihiko Takeda: Jichi Medical University, 3311-1 Yakushiji
Joachim Fandrey: Universitätsklinikum Essen, Universität Duisburg-Essen
Lukas Sommer: University of Zurich, Institute of Anatomy
Veronika Sexl: University of Veterinary Medicine
Christian Stockmann: University of Zurich, Institute of Anatomy

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25065-w

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