Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis
Pranvera Sadiku, Joseph Willson, Eilíse M. Ryan, David Sammut, Patrícia Coelho, Emily Watts, Robert Grecian, Jason M. Young, Martin A. Bewley, Simone Arienti, Ananda S. Mirchandani, Manuel A. Sánchez-García, Tyler Morrison, Ailing Zhang, Leila Reyes, Tobias Griessler, Privjyot Jheeta, Gordon Paterson, Christopher J Graham, John P. Thomson, J. Kenneth Baillie, A. A. Roger Thompson, Jessie-May Morgan, Abel Acosta‐Sanchez, Verónica M. Dardé, Jordi Durán, Joan J. Guinovart, Giovanny Rodriguez Blanco, Alex von Kriegsheim, Richard R. Meehan, Massimiliano Mazzone, David H. Dockrell, Bart Ghesquière, Peter Carmeliet, Moira K. B. Whyte, Sarah R. Walmsley
Abstract
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.