Summary Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.
Graphical Abstract
Highlights • Neutrophils utilize gluconeogenesis (GNG) to generate glycogen stores • Glycogenesis is essential for neutrophil survival and function • Defective glycogen cycling impairs neutrophil function in COPD • Glycogen cycling underpins the metabolic specialization of neutrophils
Neutrophils are required to meet their energy demands at inflamed sites where nutrients may be limited. Sadiku et al. provide evidence of a specialized metabolism that enables neutrophils to utilize glycogen cycling for energy production. This is essential for neutrophil function and survival, and dysregulation is associated with chronic disease states.