GM-CSF Induces Inflammatory Macrophages by Regulating Glycolysis and Lipid Metabolism

YR Na, GJ Gu, D Jung, YW Kim, J Na, JS Woo, JY Cho, H Youn, SH Seok

Research output: Contribution to journalArticlepeer-review

Abstract

<jats:title>Abstract</jats:title> <jats:p>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-1high macrophages 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.</jats:p>
Original languageEnglish
Pages (from-to)4101-4109
Number of pages0
JournalThe Journal of Immunology
Volume197
Issue number10
DOIs
Publication statusPublished - 15 Nov 2016

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