Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy

Lin Wu, Kate E.R. Hollinshead, Yuhan Hao, Christy Au, Lina Kroehling, Charles Ng, Woan Yu Lin, Dayi Li, Hernandez Moura Silva, Jong Shin, Juan J. Lafaille, Richard Possemato, Michael E. Pacold, Thales Papagiannakopoulos, Alec C. Kimmelman, Rahul Satija, Dan R. Littman

Research output: Contribution to journalArticlepeer-review

Abstract

Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1. Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes.

Original languageEnglish (US)
Pages (from-to)641-654.e20
JournalCell
Volume182
Issue number3
DOIs
StatePublished - Aug 6 2020

Keywords

  • CRISPR
  • EAE
  • OXPHOS
  • autoimmunity
  • colitis
  • glycolysis
  • hypoxia
  • inflammation
  • metabolic plasticity
  • segmented filamentous bacteria
  • Mucous Membrane/immunology
  • Mitochondria/metabolism
  • Glycolysis/genetics
  • Chromatography, Gas
  • Pentose Phosphate Pathway/genetics
  • Mass Spectrometry
  • Chromatography, Liquid
  • Encephalomyelitis, Autoimmune, Experimental/genetics
  • Inflammation/genetics
  • Cell Hypoxia/genetics
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics
  • Th17 Cells/immunology
  • Glucose-6-Phosphate Isomerase/genetics
  • Single-Cell Analysis
  • Mice, Inbred C57BL
  • Oxidative Phosphorylation
  • Cytokines/deficiency
  • Clostridium Infections/immunology
  • Homeostasis/genetics
  • Chimera/genetics
  • Animals
  • RNA-Seq
  • Cell Differentiation/immunology
  • Mice

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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