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.
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We would like to thank the laboratory technicians of the muscle laboratory, and in particular B. Stoltenborg, at the Translational Metabolic Laboratory (Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre) and Mietske Wijers-Rouw (Department of Cell Biology, Radboud University Nijmegen Medical Centre) for excellent technical assistance. R.S. was supported by a VIDI grant from the The Netherlands Organisation for Scientific Research (NWO) and an EFSD Rising Star Grant. R.v.C. was supported by The European Union's Seventh Framework Programme (EU FP7) project TANDEM (HEALTH-F3-2012-305279). M.G.N. was supported by an ERC Consolidator Grant (no. 310372) and a Spinoza Award (NWO).
The authors declare no competing financial interests.
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Lachmandas, E., Boutens, L., Ratter, J. et al. Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes. Nat Microbiol 2, 16246 (2017). https://doi.org/10.1038/nmicrobiol.2016.246
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