Interleukin-17 governs hypoxic adaptation of injured epithelium.
Science
; 377(6602): eabg9302, 2022 07 08.
Article
en En
| MEDLINE
| ID: mdl-35709248
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Cicatrización de Heridas
/
Interleucina-17
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Subunidad alfa del Factor 1 Inducible por Hipoxia
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Receptores de Interleucina-17
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Hipoxia
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Science
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos