TY - JOUR
T1 - Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy
AU - Wu, Lin
AU - Hollinshead, Kate E.R.
AU - Hao, Yuhan
AU - Au, Christy
AU - Kroehling, Lina
AU - Ng, Charles
AU - Lin, Woan Yu
AU - Li, Dayi
AU - Silva, Hernandez Moura
AU - Shin, Jong
AU - Lafaille, Juan J.
AU - Possemato, Richard
AU - Pacold, Michael E.
AU - Papagiannakopoulos, Thales
AU - Kimmelman, Alec C.
AU - Satija, Rahul
AU - Littman, Dan R.
N1 - Funding Information:
We thank the NYU Langone Genome Technology Center for expert library preparation and sequencing. This shared resource is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center . We thank Drew R. Jones and Rebecca E. Rose in the NYU Metabolomics Laboratory for helpful discussion and aid with LC-MS data generation and analysis. We thank S.Y. Kim in the NYU Rodent Genetic Engineering Laboratory (RGEL) for generating the Tpi1 conditional KO mice. We thank Anne R. Bresnick (Department of Biochemistry, Albert Einstein College of Medicine) for sharing the S100a4 mutant mice. This work was supported by National Multiple Sclerosis Society Fellowship FG 2089-A-1 (L.W.), Immunology and Inflammation training grant T32AI100853 (C.N.), NIH grant R01AI121436 (D.R.L.), the Howard Hughes Medical Institute (D.R.L.), and the Helen and Martin Kimmel Center for Biology and Medicine (D.R.L.)
Funding Information:
We thank the NYU Langone Genome Technology Center for expert library preparation and sequencing. This shared resource is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. We thank Drew R. Jones and Rebecca E. Rose in the NYU Metabolomics Laboratory for helpful discussion and aid with LC-MS data generation and analysis. We thank S.Y. Kim in the NYU Rodent Genetic Engineering Laboratory (RGEL) for generating the Tpi1 conditional KO mice. We thank Anne R. Bresnick (Department of Biochemistry, Albert Einstein College of Medicine) for sharing the S100a4 mutant mice. This work was supported by National Multiple Sclerosis Society Fellowship FG 2089-A-1 (L.W.), Immunology and Inflammation training grant T32AI100853 (C.N.), NIH grant R01AI121436 (D.R.L.), the Howard Hughes Medical Institute (D.R.L.), and the Helen and Martin Kimmel Center for Biology and Medicine (D.R.L.), L.W. and D.R.L. conceived the project and wrote the manuscript. L.W. designed, performed experiments, and analyzed the data. L.W. and K.E.R.H. designed and performed the GC-MS flux, tracing, and seahorse experiments, and analyzed the data. Y.H. and R.S. analyzed the scRNA-seq data. L.K. analyzed the bulk RNA-seq data. C.A. W.-Y.L. D.L. and H.M.S. helped with mouse experiments. C.N. and W.-Y.L. helped with the development of the CRISPR/Cas9 transfection method. J.S. and R.P. helped with GC-MS experiments. K.E.R.H. J.J.L. R.P. M.E.P. T.P. and A.C.K. assisted with the analysis and interpretation of the metabolic data. K.E.R.H. H.M.S. S.J. J.J.L. R.P. M.E.P. T.P. A.C.K. and R.S. edited the manuscript. D.R.L. supervised the work. D.R.L. consults and has equity interest in Chemocentryx, Vedanta, and Pfizer Pharmaceuticals. The NYU School of Medicine has filed a provisional patent application related to this work.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/8/6
Y1 - 2020/8/6
N2 - 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.
AB - 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.
KW - CRISPR
KW - EAE
KW - OXPHOS
KW - autoimmunity
KW - colitis
KW - glycolysis
KW - hypoxia
KW - inflammation
KW - metabolic plasticity
KW - segmented filamentous bacteria
KW - Mucous Membrane/immunology
KW - Mitochondria/metabolism
KW - Glycolysis/genetics
KW - Chromatography, Gas
KW - Pentose Phosphate Pathway/genetics
KW - Mass Spectrometry
KW - Chromatography, Liquid
KW - Encephalomyelitis, Autoimmune, Experimental/genetics
KW - Inflammation/genetics
KW - Cell Hypoxia/genetics
KW - Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics
KW - Th17 Cells/immunology
KW - Glucose-6-Phosphate Isomerase/genetics
KW - Single-Cell Analysis
KW - Mice, Inbred C57BL
KW - Oxidative Phosphorylation
KW - Cytokines/deficiency
KW - Clostridium Infections/immunology
KW - Homeostasis/genetics
KW - Chimera/genetics
KW - Animals
KW - RNA-Seq
KW - Cell Differentiation/immunology
KW - Mice
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U2 - 10.1016/j.cell.2020.06.014
DO - 10.1016/j.cell.2020.06.014
M3 - Article
C2 - 32615085
AN - SCOPUS:85087996358
VL - 182
SP - 641-654.e20
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -