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- Piotr Konieczny
- Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
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- Yue Xing
- Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
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- Ikjot Sidhu
- Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
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- Ipsita Subudhi
- Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
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- Kody P. Mansfield
- Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
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- Brandon Hsieh
- Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
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- Douglas E. Biancur
- Department of Radiation Oncology and Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
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- Samantha B. Larsen
- Neuroscience Institute, New York University Langone Health, New York, NY 10016, USA.
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- Michael Cammer
- Microscopy Laboratory, New York University Langone Health, New York, NY 10016, USA.
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- Dongqing Li
- Dermatology and Venereology Division, Department of Medicine, Solna Center for Molecular Medicine, Ming Wai Lau Centre for Reparative Medicine, Karolinska Institute, 17176 Stockholm, Sweden.
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- Ning Xu Landén
- Dermatology and Venereology Division, Department of Medicine, Solna Center for Molecular Medicine, Ming Wai Lau Centre for Reparative Medicine, Karolinska Institute, 17176 Stockholm, Sweden.
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- Cynthia Loomis
- Experimental Pathology Research Laboratory, New York University Langone Health, New York, NY 10016, USA.
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- Adriana Heguy
- Genome Technology Center, New York University Langone Health, New York, NY 10016, USA.
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- Anastasia N. Tikhonova
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
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- Aristotelis Tsirigos
- Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
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- Shruti Naik
- Department of Pathology, New York University Langone Health, New York, NY 10016, USA.
説明
<jats:p> 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 <jats:sup>+</jats:sup> (RORγt <jats:sup>+</jats:sup> ) 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. </jats:p>
収録刊行物
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- Science
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Science 377 (6602), eabg9302-, 2022-07-08
American Association for the Advancement of Science (AAAS)