Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization

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

Research output: Contribution to journalArticlepeer-review

570 Scopus citations

Abstract

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. 13C-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.

Original languageEnglish
Pages (from-to)419-430
Number of pages12
JournalImmunity
Volume42
Issue number3
DOIs
StatePublished - Mar 17 2015

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