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

Cell. 2020 Aug 6;182(3):641-654.e20. doi: 10.1016/j.cell.2020.06.014. Epub 2020 Jul 1.

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.

Keywords: CRISPR; EAE; OXPHOS; autoimmunity; colitis; glycolysis; hypoxia; inflammation; metabolic plasticity; segmented filamentous bacteria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / immunology*
  • Cell Hypoxia / genetics
  • Cell Hypoxia / immunology
  • Chimera / genetics
  • Chromatography, Gas
  • Chromatography, Liquid
  • Clostridium Infections / immunology
  • Cytokines / deficiency
  • Cytokines / genetics
  • Cytokines / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Glucose-6-Phosphate Isomerase / genetics
  • Glucose-6-Phosphate Isomerase / metabolism*
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / genetics
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
  • Glycolysis / genetics*
  • Glycolysis / immunology
  • Homeostasis / genetics
  • Homeostasis / immunology
  • Inflammation / genetics
  • Inflammation / immunology
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Mucous Membrane / immunology
  • Mucous Membrane / metabolism
  • Mucous Membrane / microbiology
  • Oxidative Phosphorylation*
  • Pentose Phosphate Pathway / genetics
  • Pentose Phosphate Pathway / immunology
  • Pentose Phosphate Pathway / physiology*
  • RNA-Seq
  • Single-Cell Analysis
  • Th17 Cells / immunology
  • Th17 Cells / metabolism*
  • Th17 Cells / pathology

Substances

  • Cytokines
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • Glucose-6-Phosphate Isomerase
  • Gpi1 protein, mouse