Interleukin-17 governs hypoxic adaptation of injured epithelium.
Science
; 377(6602): eabg9302, 2022 07 08.
Article
de 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Cicatrisation de plaie
/
Interleukine-17
/
Sous-unité alpha du facteur-1 induit par l'hypoxie
/
Récepteurs à l'interleukine-17
/
Hypoxie
Limites:
Animals
/
Humans
Langue:
En
Journal:
Science
Année:
2022
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique