title: GM-CSF Induces Inflammatory Macrophages by Regulating Glycolysis and Lipid Metabolism.
abstract: GM-CSF induces proinflammatory macrophages, but the underlying mechanisms have not been studied thus far. In this study, we investigated the mechanisms of how GM-CSF induces inflammatory macrophages. First, we observed that GM-CSF increased the extent of LPS-induced acute glycolysis in murine bone marrow-derived macrophages. This directly correlates with an inflammatory phenotype because glycolysis inhibition by 2-deoxyglucose abolished GM-CSF-mediated increase of TNF-α, IL-1β, IL-6, and IL-12p70 synthesis upon LPS stimulation. Increased glycolytic capacity is due to de novo synthesis of glucose transporter (GLUT)-1, -3, and -4, as well as c-myc. Meanwhile, GM-CSF increased 3-hydroxy-3-methyl-glutaryl-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway. Inhibition of acute glycolysis or 3-hydroxy-3-methyl-glutaryl-CoA reductase abrogated the inflammatory effects of GM-CSF priming in macrophages. Finally, mice with inflamed colons exposed to dextran sodium sulfate containing GLUT-1highmacrophages led to massive uptake of [18F]-fluorodeoxyglucose, but GM-CSF neutralization reduced the positron-emission tomography signal in the intestine and also decreased GLUT-1 expression in colonic macrophages. Collectively, our results reveal glycolysis and lipid metabolism created by GM-CSF as the underlying metabolic constructs for the function of inflammatory macrophages.
authors.affiliation: Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Yi Rang
authors.initials: YR
authors.lastname: Na
authors.affiliation: Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Gyo Jeong
authors.identifier: 0000-0003-0521-4270
authors.initials: GJ
authors.lastname: Gu
authors.affiliation: Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Daun
authors.initials: D
authors.lastname: Jung
authors.affiliation: Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Young Won
authors.identifier: 0000-0002-8326-8904
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Juri
authors.identifier: 0000-0002-1992-0961
authors.initials: J
authors.lastname: Na
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 110-799, South Korea; and.
authors.forename: Jin Sun
authors.identifier: 0000-0002-5577-3751
authors.initials: JS
authors.lastname: Woo
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 110-799, South Korea; and.
authors.forename: Joo Youn
authors.identifier: 0000-0001-9270-8273
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Cancer Imaging Center, Seoul National University Hospital, Seoul 110-799, South Korea.
authors.forename: Hyewon
authors.identifier: 0000-0003-1006-2689
authors.initials: H
authors.lastname: Youn
authors.affiliation: Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea; lamseok@snu.ac.kr.
authors.forename: Seung Hyeok
authors.initials: SH
authors.lastname: Seok
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D003847:Deoxyglucose / Q000494:pharmacology; D019788:Fluorodeoxyglucose F18; D016259:Genes, myc / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics; D006019:Glycolysis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000502:physiology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D050356:Lipid Metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D049268:Positron-Emission Tomography; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D051272:Glucose Transporter Type 1; D053583:Interleukin-1beta; C495678:Slc2a1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019788:Fluorodeoxyglucose F18; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003847:Deoxyglucose; D013869:Thiolester Hydrolases; C032375:hydroxymethylgutaryl-CoA hydrolase