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,
Daniël R. Faber,
Bauke V. Schomakers,
Michel van Weeghel,
Alex F. de Vos,
Brendon P. Scicluna,
Riekelt H. Houtkooper,
W. Joost Wiersinga,
Tom van der Poll
Affiliations
Alex R. Schuurman
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Corresponding author
Joe M. Butler
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Erik H.A. Michels
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Natasja A. Otto
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Xanthe Brands
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Bastiaan W. Haak
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Fabrice Uhel
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Augustijn M. Klarenbeek
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Daniël R. Faber
BovenIJ Hospital, Statenjachtstraat 1, 1034 CS Amsterdam, the Netherlands
Bauke V. Schomakers
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, 1105 AZ Amsterdam, the Netherlands
Michel van Weeghel
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, 1105 AZ Amsterdam, the Netherlands
Alex F. de Vos
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Brendon P. Scicluna
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei Hospital, University of Malta, Msida, Malta
Riekelt H. Houtkooper
Amsterdam Gastroenterology Endocrinology and Metabolism Institute, 1105 AZ Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences Institute, 1105 AZ Amsterdam, the Netherlands
W. Joost Wiersinga
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Division of Infectious Diseases, Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Tom van der Poll
Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Division of Infectious Diseases, Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Summary: 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.
