Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation

Immunity. 2024 Jul 9;57(7):1665-1680.e7. doi: 10.1016/j.immuni.2024.04.022. Epub 2024 May 20.

Abstract

Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.

Keywords: HIF1α; epithelium; glycolysis; inflammation; lactate; metabolism; skin; type 17 cells.

MeSH terms

  • Animals
  • Chronic Disease
  • Disease Models, Animal
  • Epithelium / immunology
  • Epithelium / metabolism
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Glycolysis*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Inflammation / immunology
  • Interleukin-17* / immunology
  • Interleukin-17* / metabolism
  • Lactic Acid / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Psoriasis / immunology
  • Psoriasis / metabolism
  • Signal Transduction / immunology
  • Skin / immunology
  • Skin / metabolism
  • Skin / pathology
  • Th17 Cells / immunology
  • Th17 Cells / metabolism

Substances

  • Interleukin-17
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Glucose Transporter Type 1
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Lactic Acid
  • Hif1a protein, mouse