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Published on: November 28, 2015
GM-CSF Induces Inflammatory Macrophages by Regulating Glycolysis and Lipid Metabolism
Yi Rang Na1, Gyo Jeong Gu1, Daun Jung1
1Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea.
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-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.
Insights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) drives inflammatory macrophages by boosting glycolysis and the mevalonate pathway. Inhibiting these metabolic processes reduces inflammation, offering potential therapeutic targets.
Area of Science:
- Immunology
- Metabolic pathways
- Cellular biology
Background:
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to induce proinflammatory macrophages.
- The precise molecular mechanisms underlying GM-CSF-induced macrophage inflammation remain largely unelucidated.
- Understanding these mechanisms is crucial for developing targeted immunotherapies.
Purpose of the Study:
- To investigate the metabolic mechanisms by which GM-CSF induces inflammatory macrophages.
- To determine the role of glycolysis and the mevalonate pathway in GM-CSF-driven macrophage activation.
- To explore the therapeutic potential of targeting these metabolic pathways in inflammatory conditions.
Main Methods:
- Murine bone marrow-derived macrophages were stimulated with GM-CSF and lipopolysaccharide (LPS).
- Glycolysis was inhibited using 2-deoxyglucose; the mevalonate pathway was inhibited using specific inhibitors.
- Glucose transporter (GLUT) and c-myc expression were assessed.
- Dextran sodium sulfate (DSS)-induced colitis mouse models were used, with analysis of GLUT-1 expression and positron emission tomography (PET) imaging.
Main Results:
- GM-CSF significantly increased LPS-induced glycolysis and the expression of GLUT-1, -3, -4, and c-myc.
- Inhibition of glycolysis or the mevalonate pathway abrogated GM-CSF-mediated pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6, IL-12p70).
- In vivo studies showed increased [18F]-fluorodeoxyglucose uptake in GLUT-1high macrophages in inflamed colons, which was reduced by GM-CSF neutralization.
Conclusions:
- GM-CSF primes macrophages for inflammation by enhancing glycolysis and the mevalonate pathway.
- Targeting glycolysis and lipid metabolism represents a novel strategy for controlling GM-CSF-induced inflammatory macrophage functions.
- These metabolic pathways are critical determinants of inflammatory macrophage phenotype and function.
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