Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.
Immunity
; 42(3): 419-30, 2015 Mar 17.
Article
de En
| MEDLINE
| ID: mdl-25786174
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Transcription génétique
/
Réseaux de régulation génique
/
Immunité innée
/
Macrophages
/
Mitochondries
Type d'étude:
Prognostic_studies
Limites:
Animals
Langue:
En
Journal:
Immunity
Sujet du journal:
ALERGIA E IMUNOLOGIA
Année:
2015
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique