PR001860 (Project)

Description:Neutrophils could utilize a variety of metabolic sources to support their vital functions as the first responders in innate immunity. Here, using in vivo and ex vivo isotopic tracing, we quantitatively examined the contributions of different nutrients under specific conditions, and found that human circulating neutrophils, in contrast to neutrophil cell line, rely on glycogen storage as a major metabolic source under resting state, but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, which is mechanistically mediated by the rapid phosphorylation and translocation of GLUT1, that dominates the simultaneous increase in gross glycogen cycling. Shift in nutrient utilization impacts neutrophil functions in a function-specific manner: Oxidative burst depends on glucose utilization; whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen; and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism, and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance.