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

• DOI: 10.1016/j.immuni.2015.02.005
• Publication Date: 2015-03-17T19:34:30Z
• Authors: Abhishek K. Jha; Stanley Ching-Che...; Alexey Sergushichev; Vicky Lampropoulou; Yulia Ivanova; Ekaterina Loginic...; Karina Chmielewski; Kelly M. Stewart; Juliet Ashall; Bart Everts; Edward J. Pearce; Edward M. Driggers; Maxim N. Artyomov
• Keywords: Macrophage polarization; Metabolic pathway; Catabolism; Metabolic network; Crosstalk

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.