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
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.
Nat Microbiol. 2016 Dec 19;2:16246. 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.
诸如脂多糖（LPS）等微生物刺激会在免疫细胞中引发强大的代谢重编程，即所谓的瓦伯格效应。尚不清楚糖酵解增加和氧化磷酸化（OXPHOS）减少是否是遭遇病原体的单核细胞的普遍特征。利用健康供体的CD14单核细胞，我们证明大多数微生物刺激会增加糖酵解，但只有用LPS刺激Toll样受体（TLR）4才会导致OXPHOS减少。相反，其他TLR的激活，如用Pam3CysSK4（P3C）激活TLR2，会增加氧气消耗和线粒体酶活性。对用P3C与LPS刺激的单核细胞进行转录组和代谢组分析，证实了两种刺激之间不同的代谢反应，并揭示了用P3C与LPS刺激单核细胞后三羧酸循环、OXPHOS和脂质代谢途径的显著差异。在功能水平上，线粒体电子传递链复合体I的药理学抑制减少了P3C刺激而非LPS刺激的单核细胞中的细胞因子产生和吞噬作用。因此，与LPS不同，复杂的微生物刺激和TLR2配体P3C会诱导一种特定的代谢重编程模式，涉及糖酵解和OXPHOS的上调，从而激活细胞因子产生和吞噬作用等宿主防御机制。
