Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.

Abstract

Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like 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, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact 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 work 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.

Authors

Emily C Britt, Xin Qing, James A Votava, Jorgo Lika, Andrew S Wagner, Simone Shen, Nicholas Arp, Hamidullah Khan, Stefan M Schieke, Christopher D Fletcher, Anna Huttenlocher, Jing Fan

Morgridge Institute for Research, Madison, WI 53715, Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI 53706, Cell and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI 53706, University of Wisconsin Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, University of Wisconsin Carbone Cancer Center, Madison, WI 53792.