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. | PubMed

Lin Wu¹, Kate E R Hollinshead², Yuhan Hao³, Christy Au⁴, Lina Kroehling⁵, Charles Ng⁵, Woan-Yu Lin⁵, Dayi Li⁵, Hernandez Moura Silva⁵, Jong Shin⁶, Juan J Lafaille⁷, Richard Possemato⁶, Michael E Pacold², Thales Papagiannakopoulos⁶, Alec C Kimmelman², Rahul Satija³, Dan R Littman⁸

1. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA. Electronic address: lin.wu@med.nyu.edu.
2. Department of Radiation Oncology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
3. New York Genome Center, New York, NY, USA; Center for Genomics and Systems Biology, New York University, New York, NY, USA.
4. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA.
5. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA.
6. Department of Pathology, New York University School of Medicine, New York, NY, USA.
7. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA; Department of Pathology, New York University School of Medicine, New York, NY, USA.
8. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA; Department of Pathology, New York University School of Medicine, New York, NY, USA. Electronic address: dan.littman@med.nyu.edu.

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.

Presented By Lin Wu