Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy.
Cell
; 182(3): 641-654.e20, 2020 08 06.
Article
em En
| MEDLINE
| ID: mdl-32615085
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosforilação Oxidativa
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Via de Pentose Fosfato
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Diferenciação Celular
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Encefalomielite Autoimune Experimental
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Células Th17
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Glucose-6-Fosfato Isomerase
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Glicólise
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article