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Immunity. 2015 Mar 17;42(3):419-30. doi: 10.1016/j.immuni.2015.02.005.

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

Author information

1
Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
2
Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
3
Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; ITMO University, 49 Kronverksky Prospekt, Saint Petersburg 197101, Russia.
4
Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA. Electronic address: edward.driggers@generalmetabolics.com.
5
Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: martyomov@pathology.wustl.edu.

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. (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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PMID:
25786174
DOI:
10.1016/j.immuni.2015.02.005
[Indexed for MEDLINE]
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