RESUMEN

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1ß but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1ß as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1ß production during inflammation.

Asunto(s)

Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Interleucina-1beta/biosíntesis , Transducción de Señal , Ácido Succínico/metabolismo , Animales , Células de la Médula Ósea/citología , Ciclo del Ácido Cítrico/efectos de los fármacos , Desoxiglucosa/farmacología , Regulación hacia Abajo/efectos de los fármacos , Genes Mitocondriales/efectos de los fármacos , Genes Mitocondriales/genética , Glutamina/metabolismo , Glucólisis/efectos de los fármacos , Glucólisis/genética , Humanos , Inmunidad Innata/efectos de los fármacos , Inflamación/metabolismo , Interleucina-1beta/genética , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Regulación hacia Arriba/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo