2. Academic Validation
  3. GM-CSF Induces Inflammatory Macrophages by Regulating Glycolysis and Lipid Metabolism

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

  • J Immunol. 2016 Nov 15;197(10):4101-4109. doi: 10.4049/jimmunol.1600745.
Yi Rang Na 1,  Gyo Jeong Gu 1,  Daun Jung 1,  Young Won Kim 1,  Juri Na 2 3 4,  Jin Sun Woo 5,  Joo Youn Cho 5,  Hyewon Youn 3 4 6,  Seung Hyeok Seok 7
Affiliations

Affiliations

  • 1 Macrophage Laboratory, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, South Korea.
  • 2 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea.
  • 3 Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 110-799, South Korea.
  • 4 Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea.
  • 5 Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 110-799, South Korea; and.
  • 6 Cancer Imaging Center, Seoul National University Hospital, Seoul 110-799, South Korea.
  • 7 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.
PMID: 27742831 DOI: 10.4049/jimmunol.1600745
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.

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