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

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

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.

MeSH terms

  • Animals
  • Argininosuccinic Acid / immunology
  • Argininosuccinic Acid / metabolism
  • Aspartate Aminotransferase, Mitochondrial / genetics
  • Aspartate Aminotransferase, Mitochondrial / immunology
  • Aspartic Acid / immunology
  • Aspartic Acid / metabolism
  • Chemokine CCL22 / genetics
  • Chemokine CCL22 / immunology
  • Citric Acid Cycle
  • Gene Expression Regulation
  • Gene Regulatory Networks / immunology*
  • Glutamine / deficiency
  • Glycosylation
  • Immunity, Innate*
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / immunology
  • Macrophages / classification
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Metabolic Networks and Pathways / genetics
  • Metabolic Networks and Pathways / immunology
  • Mice
  • Mitochondria / genetics
  • Mitochondria / immunology
  • Mitochondria / metabolism*
  • Nitric Oxide / immunology
  • Nitric Oxide / metabolism
  • Signal Transduction
  • Transcription, Genetic / immunology*
  • Uridine Diphosphate N-Acetylglucosamine / immunology
  • Uridine Diphosphate N-Acetylglucosamine / metabolism

Substances

  • Ccl22 protein, mouse
  • Chemokine CCL22
  • Interleukin-6
  • Glutamine
  • Argininosuccinic Acid
  • Aspartic Acid
  • Nitric Oxide
  • Uridine Diphosphate N-Acetylglucosamine
  • Isocitrate Dehydrogenase
  • Aspartate Aminotransferase, Mitochondrial

Associated data

  • GEO/GSE53053