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Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy.
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.
Afiliación
  • Wu L; 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.
  • Hollinshead KER; Department of Radiation Oncology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
  • Hao Y; New York Genome Center, New York, NY, USA; Center for Genomics and Systems Biology, New York University, New York, NY, USA.
  • Au C; 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.
  • Kroehling L; The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA.
  • Ng C; The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA.
  • Lin WY; The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA.
  • Li D; The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA.
  • Silva HM; The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA.
  • Shin J; Department of Pathology, New York University School of Medicine, New York, NY, USA.
  • Lafaille JJ; 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.
  • Possemato R; Department of Pathology, New York University School of Medicine, New York, NY, USA.
  • Pacold ME; Department of Radiation Oncology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
  • Papagiannakopoulos T; Department of Pathology, New York University School of Medicine, New York, NY, USA.
  • Kimmelman AC; Department of Radiation Oncology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
  • Satija R; New York Genome Center, New York, NY, USA; Center for Genomics and Systems Biology, New York University, New York, NY, USA.
  • Littman DR; 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
Cell ; 182(3): 641-654.e20, 2020 08 06.
Article en En | MEDLINE | ID: mdl-32615085
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Vía de Pentosa Fosfato / Diferenciación Celular / Encefalomielitis Autoinmune Experimental / Células Th17 / Glucosa-6-Fosfato Isomerasa / Glucólisis Idioma: En Revista: Cell Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Vía de Pentosa Fosfato / Diferenciación Celular / Encefalomielitis Autoinmune Experimental / Células Th17 / Glucosa-6-Fosfato Isomerasa / Glucólisis Idioma: En Revista: Cell Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos