Intracellular pyruvate levels positively correlate with cytokine production capacity in tolerant monocytes from patients with pneumonia |
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| Institution: | 1. Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands;2. Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands;3. Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands;4. Core Facility Metabolomics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands;5. Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands;6. Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands;7. Laboratory of Genome Analysis, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands;8. BovenIJ hospital, Amsterdam, the Netherlands.;9. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands;10. Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands |
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| Abstract: | BackgroundCommunity-acquired pneumonia (CAP) is responsible for a high morbidity and mortality worldwide. Monocytes are essential for pathogen recognition and the initiation of an innate immune response. Immune cells induce intracellular glycolysis upon activation to support several functions.ObjectiveTo obtain insight in the metabolic profile of blood monocytes during CAP, with a focus on glycolysis and branching metabolic pathways, and to determine a possible association between intracellular metabolite levels and monocyte function.MethodsMonocytes were isolated from blood of patients with CAP within 24 h of hospital admission and from control subjects matched for age, sex and chronic comorbidities. Changes in glycolysis, oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle and the pentose phosphate pathway were investigated through RNA sequencing and metabolomics measurements. Monocytes were stimulated ex vivo with lipopolysaccharide (LPS) to determine their capacity to produce tumor necrosis factor (TNF), interleukin (IL)-1β and IL-10.Results50 patients with CAP and 25 non-infectious control subjects were studied. When compared with control monocytes, monocytes from patients showed upregulation of many genes involved in glycolysis, including PKM, the gene encoding pyruvate kinase, the rate limiting enzyme for pyruvate production. Gene set enrichment analysis of OXPHOS, the TCA cycle and the pentose phosphate pathway did not reveal differences between monocytes from patients and controls. Patients' monocytes had elevated intracellular levels of pyruvate and the TCA cycle intermediate α-ketoglutarate. Monocytes from patients were less capable of producing cytokines upon LPS stimulation. Intracellular pyruvate (but not α-ketoglutarate) concentrations positively correlated with IL-1β and IL-10 levels released by patients' (but not control) monocytes upon exposure to LPS.ConclusionThese results suggest that elevated intracellular pyruvate levels may partially maintain cytokine production capacity of hyporesponsive monocytes from patients with CAP. |
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