Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of α-ketoglutarate (αKG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high αKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, αKG contributes to endotoxin tolerance after M1 activation. This study reveals new mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming.

中文翻译：

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α-酮戊二酸通过代谢和表观遗传重编程来协调巨噬细胞的激活

谷氨酰胺代谢为巨噬细胞活化和引发理想的免疫反应提供协同支持；然而，由谷氨酰胺代谢调控的巨噬细胞活化调控的潜在机制仍不清楚。在这里，我们表明，生产的α酮戊二酸（α经由谷氨酰胺KG）是巨噬细胞的替代（M2）的活化，包括（FAO）的脂肪酸氧化的接合和M2基因的JMJD3依赖性表观重编程重要。此M2促进机构由高进一步调制α KG /琥珀酸比，而低比率加强了经典活化（M1）的巨噬细胞促炎表型。因此，αKG有助于M1激活后的内毒素耐受性。这项研究揭示了谷氨酰胺代谢通过代谢和表观遗传重编程来调节巨噬细胞免疫反应的新机制。