Rewiring of Glucose and Glycogen Metabolism in Human Neutrophils Upon Activation

Résumé du livre

Neutrophils are the first responder in immunity and exhibit applicable functional capabilities for this role. Effector functions, including oxidative burst, neutrophil extracellular trap (NET) release, and phagocytosis, kill pathogens to protect the body against infection. However, there is a metabolic cost to elicit these crucial functions, exposing the need to uncover the links between metabolic reprogramming and neutrophil function. Metabolomics analysis revealed rapid and dramatic changes in metabolism upon activation. Changes in metabolic flux were intricately linked with function. Upon activation, neutrophils altered the disruption of glucose-6-phosphate (G6P) flux, diverting it from glycolysis into the oxidative pentose phosphate pathway and recycling the carbons with reversed flux of glucose-6-phosphate isomerase, entering a metabolic mode termed the pentose cycle. This allowed for the maximum amount of NADPH generation per molecule of G6P to be used by NADPH oxidase (NOX2) to generate reactive oxygen species for the oxidative burst. Disruption of the pentose cycle altered functions downstream of oxidative burst including NET release and pathogen killing. After observing changes in the fate of glycolysis metabolites, investigation into metabolic source were probed. Unactivated neutrophils utilized an almost equal mix of extracellular glucose and intracellular glycogen to supply downstream pathways, while upon activation, preference rapidly shifted towards extracellular glucose. Evaluation of effector function fuel utilization revealed heterogeneous dependence. Oxidative burst was more dependent on glucose, early pathogen killing depended on glycogen, and NET release displayed metabolic flexibility for use of either extracellular glucose or glycogen utilization. Taken together these data upended the simplistic view of neutrophil metabolism and displayed unique metabolic rewiring in immune cells.