Interleukin-17 governs hypoxic adaptation of injured epithelium

  • Science. 2022 Jul 8;377(6602):eabg9302. doi: 10.1126/science.abg9302.
Piotr Konieczny   #  1 ,  Yue Xing   #  1 ,  Ikjot Sidhu  1  2 ,  Ipsita Subudhi  1 ,  Kody P Mansfield  1 ,  Brandon Hsieh  1 ,  Douglas E Biancur  3 ,  Samantha B Larsen  4 ,  Michael Cammer  5 ,  Dongqing Li  6 ,  Ning Xu Landén  6 ,  Cynthia Loomis  7 ,  Adriana Heguy  8 ,  Anastasia N Tikhonova  9 ,  Aristotelis Tsirigos  1  2 ,  Shruti Naik  1  10
Affiliations
  • 1. Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
  • 2. Applied Bioinformatics Laboratory, New York University Langone Health, New York, NY 10016, USA.
  • 3. Department of Radiation Oncology and Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
  • 4. Neuroscience Institute, New York University Langone Health, New York, NY 10016, USA.
  • 5. Microscopy Laboratory, New York University Langone Health, New York, NY 10016, USA.
  • 6. Dermatology and Venereology Division, Department of Medicine, Solna Center for Molecular Medicine, Ming Wai Lau Centre for Reparative Medicine, Karolinska Institute, 17176 Stockholm, Sweden.
  • 7. Experimental Pathology Research Laboratory, New York University Langone Health, New York, NY 10016, USA.
  • 8. Genome Technology Center, New York University Langone Health, New York, NY 10016, USA.
  • 9. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
  • 10. Department of Medicine, Ronald O. Perelman Department of Dermatology, and Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
  • # Contributed equally.
PMID: 35709248 DOI: 10.1126/science.abg9302
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.

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