Network Integration of Parallel Metabolic and Transcriptional Data Reveals Metabolic Modules that Regulate Macrophage Polarization
2015; Cell Press; Volume: 42; Issue: 3 Linguagem: Inglês
10.1016/j.immuni.2015.02.005
ISSN1097-4180
AutoresAbhishek 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,
Tópico(s)Single-cell and spatial transcriptomics
ResumoMacrophage 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.
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