Author:
Wu Lin,Hollinshead Kate E.R.,Hao Yuhan,Au Christy,Kroehling Lina,Ng Charles,Lin Woan-Yu,Li Dayi,Silva Hernandez Moura,Shin Jong,Lafaille Juan J.,Possemato Richard,Pacold Michael E.,Papagiannakopoulos Thales,Kimmelman Alec C.,Satija Rahul,Littman Dan R.
Abstract
SummaryTargeting 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.
Publisher
Cold Spring Harbor Laboratory
Reference95 articles.
1. Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T Cells
2. Cutting Edge: IL-23 Receptor GFP Reporter Mice Reveal Distinct Populations of IL-17-Producing Cells
3. Study of the molecular defects in glucose phosphate isomerase-deficient patients affected by chronic hemolytic anemia;Blood,1996
4. Becht, E. , McInnes, L. , Healy, J. , Dutertre, C.A. , Kwok, I.W.H. , Ng, L.G. , Ginhoux, F. , and Newell, E.W . (2018). Dimensionality reduction for visualizing single-cell data using UMAP. Nat Biotechnol.
5. Myelin Oligodendrocyte Glycoprotein–specific T Cell Receptor Transgenic Mice Develop Spontaneous Autoimmune Optic Neuritis