RESUMO
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.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-1beta/biossíntese , Transdução de Sinais , Ácido Succínico/metabolismo , Animais , Células da Medula Óssea/citologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Desoxiglucose/farmacologia , Regulação para Baixo/efeitos dos fármacos , Genes Mitocondriais/efeitos dos fármacos , Genes Mitocondriais/genética , Glutamina/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/metabolismo , Interleucina-1beta/genética , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Regulação para Cima/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
Monovision has been a controversial contact lens correction modality for over 30 years. This paper addresses the major issues and concerns and considers them in the light of patient safety, visual efficiency and practitioner liability.
