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

AK Jha, SCC Huang, A Sergushichev, V Lampropoulou… - Immunity, 2015 - cell.com
AK Jha, SCC Huang, A Sergushichev, V Lampropoulou, Y Ivanova, E Loginicheva…
Immunity, 2015cell.com
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 …
Summary
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.
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