Interleukin-17 governs hypoxic adaptation of injured epithelium

Author:

Konieczny Piotr1ORCID,Xing Yue1ORCID,Sidhu Ikjot12,Subudhi Ipsita1ORCID,Mansfield Kody P.1ORCID,Hsieh Brandon1ORCID,Biancur Douglas E.3,Larsen Samantha B.4ORCID,Cammer Michael5ORCID,Li Dongqing6ORCID,Landén Ning Xu6ORCID,Loomis Cynthia7,Heguy Adriana8ORCID,Tikhonova Anastasia N.9ORCID,Tsirigos Aristotelis12ORCID,Naik Shruti110ORCID

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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