title: Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.
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.
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Jha
authors.affiliation: Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Stanley Ching-Cheng
authors.initials: SC
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Alexey
authors.initials: A
authors.lastname: Sergushichev
authors.affiliation: Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Vicky
authors.initials: V
authors.lastname: Lampropoulou
authors.affiliation: Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ivanova
authors.affiliation: Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Loginicheva
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Chmielewski
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Stewart
authors.affiliation: Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Juliet
authors.initials: J
authors.lastname: Ashall
authors.affiliation: Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Bart
authors.initials: B
authors.lastname: Everts
authors.affiliation: Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA. Electronic address: edward.driggers@generalmetabolics.com.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Driggers
authors.affiliation: Department of Pathology & Immunology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: martyomov@pathology.wustl.edu.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
mesh_terms: D000818:Animals; D001125:Argininosuccinic Acid / Q000276:immunology / Q000378:metabolism; D024442:Aspartate Aminotransferase, Mitochondrial / Q000235:genetics / Q000276:immunology; D001224:Aspartic Acid / Q000276:immunology / Q000378:metabolism; D054422:Chemokine CCL22 / Q000235:genetics / Q000276:immunology; D002952:Citric Acid Cycle; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000276:immunology*; D005973:Glutamine / Q000172:deficiency; D006031:Glycosylation; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000145:classification / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000276:immunology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000276:immunology*; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000276:immunology / Q000378:metabolism
chemical_list: C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D015850:Interleukin-6; D005973:Glutamine; D001125:Argininosuccinic Acid; D001224:Aspartic Acid; D009569:Nitric Oxide; D014537:Uridine Diphosphate N-Acetylglucosamine; D007521:Isocitrate Dehydrogenase; D024442:Aspartate Aminotransferase, Mitochondrial