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Niche-selective inhibition of pathogenic Th17 cells by targeting metabolic redundancy

By 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 Lafaille, Richard Possemato, Michael E. Pacold, Thales Papagiannakopoulos, Alec C Kimmelman, Rahul Satija, Dan Littman

Posted 29 Nov 2019
bioRxiv DOI: 10.1101/857961 (published DOI: 10.1016/j.cell.2020.06.014)

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. ### Competing Interest Statement The authors have declared no competing interest.

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