Toll-like receptor (TLR) activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remains unknown. Here, we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Shortly after TLR4 activation, macrophages increased glycolysis and tricarboxylic acid (TCA) cycle volume. Metabolic tracing studies revealed that TLR signaling redirected metabolic fluxes to generate acetyl-Coenzyme A (CoA) from glucose resulting in augmented histone acetylation. Signaling through the adaptor proteins MyD88 and TRIF resulted in activation of ATP-citrate lyase, which in turn facilitated the induction of distinct LPS-inducible gene sets. We postulate that metabolic licensing of histone acetylation provides another layer of control that serves to fine-tune transcriptional responses downstream of TLR activation. Our work highlights the potential of targeting the metabolic-epigenetic axis in inflammatory settings.

中文翻译：

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Toll样受体信号转导巨噬细胞代谢，并通过ATP柠檬酸裂解酶促进组蛋白乙酰化。

Toll样受体（TLR）激活通过激活时间定义的转录级联反应在巨噬细胞中诱导炎症反应。TLR激活后发生的细胞代谢的同时变化是否影响转录反应的质量仍然未知。在这里，我们研究了巨噬细胞在激活后如何早期利用其代谢来调节TLR诱导的基因诱导。TLR4激活后不久，巨噬细胞增加了糖酵解和三羧酸（TCA）循环量。代谢追踪研究表明，TLR信号转导代谢通量以从葡萄糖生成乙酰辅酶A（CoA），从而导致组蛋白乙酰化增强。通过衔接子蛋白MyD88和TRIF发出的信号导致ATP柠檬酸裂解酶的激活，反过来，这有助于诱导不同的LPS诱导基因集。我们推测，组蛋白乙酰化的代谢许可提供了另一层控制，可用于微调TLR激活下游的转录反应。我们的工作突出了在炎症环境中靶向代谢表观遗传轴的潜力。