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-1 macrophages led to massive uptake of [F]-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.

Fine tuning of immunometabolism for the treatment of rheumatic diseases

“…The ability to mature and gain effector function (including the differentiation of monocytes into osteoclasts) is, however, essential for these cells. Macrophages and dendritic cells are activated in response to PAMPs and DAMPs, including TLRs, and this activation increases glycolysis to promote inflammatory function and maturation 31–35 . TLR signalling through serine/threonine-protein kinase TBK1 leads to AKT activation and mTORC1 signalling to promote this glycolytic switch 36–38 .…”

A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

“…production, phagocytosis and pathogen killing [68][69][70] . Pro-inflammatory T cells are known to be associated with negative disease outcome, as GM-CSF production can drive disease progression in autoimmune disorders 71 , neurological disease 72 and skin hyperinflammation 73 .…”

The involvement of GM-CSF deficiencies in parallel pathways of pulmonary alveolar proteinosis and the alcoholic lung

“…For example, studies have shown that the behavior of macrophages from different tissues can be readily influenced by either altering their exposure to different metabolic substrates or by directing cells to utilize different metabolic pathways [50]. In macrophage populations outside the lung, it has been shown that cells often rely on glycolysis for driving M1 behaviors whereas M2 responses are often dependent on the use of mitochondrial respiration [50, 51]. Furthermore, M2 macrophages appear to preferentially utilize fatty acids as a substrate, which requires the use of mitochondria for β-oxidation Interestingly, recent work has demonstrated that GM-CSF itself can direct cells to utilize glycolysis, suggesting that M2 polarization in the setting of chronic alcohol exposure could be a direct consequence to the loss of GM-CSF signaling [51].…”

“…In macrophage populations outside the lung, it has been shown that cells often rely on glycolysis for driving M1 behaviors whereas M2 responses are often dependent on the use of mitochondrial respiration [50, 51]. Furthermore, M2 macrophages appear to preferentially utilize fatty acids as a substrate, which requires the use of mitochondria for β-oxidation Interestingly, recent work has demonstrated that GM-CSF itself can direct cells to utilize glycolysis, suggesting that M2 polarization in the setting of chronic alcohol exposure could be a direct consequence to the loss of GM-CSF signaling [51]. Alternatively, it is possible that M2 polarization is just a byproduct of intracellular lipid accumulation and increased mitochondrial fatty acid β-oxidation.…”