title: Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes.
abstract: Microbial stimuli such as lipopolysaccharide (LPS) induce robust metabolic rewiring in immune cells known as the Warburg effect. It is unknown whether this increase in glycolysis and decrease in oxidative phosphorylation (OXPHOS) is a general characteristic of monocytes that have encountered a pathogen. Using CD14+monocytes from healthy donors, we demonstrated that most microbial stimuli increased glycolysis, but that only stimulation of Toll-like receptor (TLR) 4 with LPS led to a decrease in OXPHOS. Instead, activation of other TLRs, such as TLR2 activation by Pam3CysSK4 (P3C), increased oxygen consumption and mitochondrial enzyme activity. Transcriptome and metabolome analysis of monocytes stimulated with P3C versus LPS confirmed the divergent metabolic responses between both stimuli, and revealed significant differences in the tricarboxylic acid cycle, OXPHOS and lipid metabolism pathways following stimulation of monocytes with P3C versus LPS. At a functional level, pharmacological inhibition of complex I of the mitochondrial electron transport chain diminished cytokine production and phagocytosis in P3C- but not LPS-stimulated monocytes. Thus, unlike LPS, complex microbial stimuli and the TLR2 ligand P3C induce a specific pattern of metabolic rewiring that involves upregulation of both glycolysis and OXPHOS, which enables activation of host defence mechanisms such as cytokine production and phagocytosis.
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Ekta
authors.initials: E
authors.lastname: Lachmandas
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.|Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, 6708 WE, Wageningen, The Netherlands.
authors.forename: Lily
authors.initials: L
authors.lastname: Boutens
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.|Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, 6708 WE, Wageningen, The Netherlands.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Ratter
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Hijmans
authors.affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, 6708 WE, Wageningen, The Netherlands.
authors.forename: Guido J
authors.identifier: http://orcid.org/0000-0003-1954-3542
authors.initials: GJ
authors.lastname: Hooiveld
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Pediatrics, Radboud Center for Mitochondrial Medicine, 774 Translational Metabolic Laboratory, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 1105 AZ, Nijmegen, The Netherlands.
authors.forename: Jack A M
authors.initials: JA
authors.lastname: Fransen
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.|Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, 6708 WE, Wageningen, The Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra