Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Immunity. 2015 Mar 17;42(3):419-30. doi: 10.1016/j.immuni.2015.02.005.
Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.
巨噬细胞极化涉及协调的代谢和转录重编程，目前仅部分了解。通过使用集成的高通量转录代谢谱分析和分析管道，我们描述了在小鼠巨噬细胞 M1 和 M2 极化过程中的系统变化。发现 M2 极化激活谷氨酰胺分解代谢和 UDP-GlcNAc 相关模块。相应地，谷氨酰胺剥夺或 N-糖基化抑制降低了 M2 极化和趋化因子 CCL22 的产生。在 M1 巨噬细胞中，我们在将异柠檬酸转化为α-酮戊二酸的酶 IDH 处发现了代谢断裂，为 TCA 循环碎裂提供了机制解释。(13)C 示踪研究表明存在活跃的天冬氨酸-精氨酸穿梭变体，可补偿这种断裂。一致地，天冬氨酸转氨酶的抑制，穿梭的关键酶，抑制了 M1 巨噬细胞中一氧化氮和白细胞介素-6 的产生，同时促进了线粒体呼吸。这种系统方法提供了支持巨噬细胞极化的生理模块的高度综合图景，确定了两种巨噬细胞表型的潜在药理控制点。
