Network Integration of Parallel Metabolic and Transcriptional Data Reveals Metabolic Modules that Regulate Macrophage Polarization

作者：Jha, Abhishek K.; Huang, Stanley Ching-Cheng; Sergushichev, Alexey; Lampropoulou, Vicky; Ivanova, Yulia; Loginicheva, Ekaterina; Chmielewski, Karina; Stewart, Kelly M.; Ashall, Juliet; Everts, Bart; Pearce, Edward J.; Driggers, Edward M.^*; Artyomov, Maxim N.

来源：Immunity, 2015, 42(3): 419-430.

DOI：10.1016/j.immuni.2015.02.005

• NITRIC-OXIDE
• GLYCOSYLATION
• IMMUNITY
• INNATE

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.

• 出版日期2015-3-17