Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes

• Published in: Nature microbiology Vol. 2; no. 3; p. 16246
• Main Authors: Lachmandas, Ekta, Boutens, Lily, Ratter, Jacqueline M., Hijmans, Anneke, Hooiveld, Guido J., Joosten, Leo A. B., Rodenburg, Richard J., Fransen, Jack A. M., Houtkooper, Riekelt H., van Crevel, Reinout, Netea, Mihai G., Stienstra, Rinke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.12.2016; Nature Publishing Group
• Subjects: 631/250/2504/342; 631/250/254; 631/326/41/2533; Biomedical and Life Sciences; CD14 antigen; Chair Nutrition Metabolism and Genomics; Cytokines; Electron transport chain; Enzymatic activity; Gene expression; Glycolysis; HNE Nutrition, Metabolism and Genomics; HNE Voeding, Metabolisme en Genomics; Infectious Diseases; Life Sciences; Lipid metabolism; Lipopolysaccharides; Medical Microbiology; Metabolic response; Metabolism; Microbiology; Mitochondria; Monocytes; Nutrition, Metabolism and Genomics; Oxidative phosphorylation; Oxygen consumption; Parasitology; Phagocytosis; Phosphorylation; Signal transduction; TLR2 protein; Toll-like receptors; Tricarboxylic acid cycle; Virology; VLAG; Voeding, Metabolisme en Genomica
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/nmicrobiol.2016.246

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. While stimulation of TLR4 with LPS leads to an increase in glycolysis and a decrease in oxidative phosphorylation, complex microbial stimuli and the TLR2 ligand P3C induce upregulation of both glycolysis and oxidative phosphorylation.