1. Academic Validation
  2. Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation

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

  • Immunity. 2024 May 14:S1074-7613(24)00227-9. doi: 10.1016/j.immuni.2024.04.022.
Ipsita Subudhi 1 Piotr Konieczny 2 Aleksandr Prystupa 3 Rochelle L Castillo 4 Erica Sze-Tu 1 Yue Xing 1 Daniel Rosenblum 1 Ilana Reznikov 1 Ikjot Sidhu 3 Cynthia Loomis 1 Catherine P Lu 5 Niroshana Anandasabapathy 6 Mayte Suárez-Fariñas 7 Johann E Gudjonsson 8 Aristotelis Tsirigos 9 Jose U Scher 10 Shruti Naik 11
Affiliations

Affiliations

  • 1 Department of Pathology, NYU Langone Health, New York, NY 10016, USA.
  • 2 Department of Pathology, NYU Langone Health, New York, NY 10016, USA. Electronic address: [email protected].
  • 3 Department of Pathology, NYU Langone Health, New York, NY 10016, USA; Applied Bioinformatics Laboratories, NYU Langone Health, New York, NY 10016, USA.
  • 4 Division of Rheumatology, Department of Medicine, NYU Langone Health, New York, NY 10016, USA; Psoriatic Arthritis Center, NYU Langone Health, New York, NY 10016, USA.
  • 5 The Hansjörg Wyss Department of Plastic Surgery and Department of Cell Biology, NYU Langone Health, New York, NY 10016, USA.
  • 6 Department of Dermatology, Weill Cornell Medicine, New York, NY 10026, USA.
  • 7 Department of Genetics and Genomic Science, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8 Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9 Applied Bioinformatics Laboratories, NYU Langone Health, New York, NY 10016, USA; Precision Medicine Institute, Department of Medicine, NYU Langone Health, New York, NY 10016, USA.
  • 10 Division of Rheumatology, Department of Medicine, NYU Langone Health, New York, NY 10016, USA; NYU Colton Center for Autoimmunity, Department of Medicine, NYU Langone Health, New York, NY 10016, USA.
  • 11 Department of Pathology, NYU Langone Health, New York, NY 10016, USA; NYU Colton Center for Autoimmunity, Department of Medicine, NYU Langone Health, New York, NY 10016, USA; Ronald O. Perelman Department of Dermatology, Department of Medicine, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA. Electronic address: [email protected].
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.

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