Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia
Alex R. Schuurman, Joe M. Butler, Erik H.A. Michels, Natasja A. Otto, Xanthe Brands, Bastiaan W. Haak, Fabrice Uhel, Augustijn M. Klarenbeek, Daniel Faber, Bauke V. Schomakers, Michel van Weeghel, Alex F. de Vos, Brendon P. Scicluna, Riekelt H. Houtkooper, W. Joost Wiersinga, Tom van der Poll
Abstract
Neutrophils are potent immune cells with key antimicrobial functions. Previous in vitro work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection. Here, we combined flow cytometry, stimulation assays, transcriptomics, and metabolomics to investigate the link between inflammatory and metabolic pathways in blood neutrophils of patients with community-acquired pneumonia. Patients' neutrophils, relative to neutrophils from age- and sex- matched controls, showed increased degranulation upon ex vivo stimulation, and portrayed distinct upregulation of inflammatory transcriptional programs. This neutrophil phenotype was accompanied by a high-energy state with increased intracellular ATP content, and transcriptomic and metabolic upregulation of glycolysis and glycogenolysis. One month after hospital admission, these metabolic and transcriptomic changes were largely normalized. These data elucidate the molecular programs that underpin a balanced, yet primed state of blood neutrophils during pneumonia.