Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes
Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes
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DOI：
10.1038/nmicrobiol.2016.246
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发表时间：
2017-03-01
影响因子：
28.3
通讯作者：
Stienstra, Rinke
中科院分区：
文献类型：
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作者：
Lachmandas, Ekta;Boutens, Lily;Stienstra, Rinke
微生物刺激如脂多糖（LPS）诱导免疫细胞中的强大代谢重新布线，称为瓦尔堡效应。目前尚不清楚这种糖酵解的增加和氧化磷酸化（OXPHOS）的减少是否是遇到病原体的单核细胞的一般特征。使用来自健康供体的CD 14（+）单核细胞，我们证明大多数微生物刺激增加糖酵解，但只有LPS刺激Toll样受体（TLR）4导致OXPHOS减少。相反，其他TLR的激活，如Pam 3CysSK 4（P3 C）激活的TLR 2，增加了氧消耗和线粒体酶活性。转录组和代谢组学分析的单核细胞刺激与P3 C与LPS证实了不同的代谢反应之间的刺激，并揭示了显着差异的三羧酸循环，OXPHOS和脂质代谢途径刺激单核细胞与P3 C与LPS。在功能水平上，线粒体电子传递链复合物I的药理学抑制减少了P3 C-但不是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，复杂的微生物刺激物和TLR 2配体P3 C诱导特定模式的代谢重新布线，其涉及糖酵解和OXPHOS的上调，这使得宿主防御机制如细胞因子产生和吞噬作用的激活成为可能。
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.