Differential regulation of macrophage glucose metabolism by macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: Implications for ¹⁸F FDG PET imaging of vessel wall inflammation

Purpose: To determine the divergence of immunometabolic phenotypes of macrophages stimulated with macrophage colony-stimulating factor (MCSF) and granulocyte-M-CSF (GM-CSF) and its implications for fluorine 18 (¹⁸F) fluorodeoxyglucose (FDG) imaging of atherosclerosis. Materials and Methods: This study was approved by the animal care committee. Uptake of 2-deoxyglucose and various indexes of oxidative and glycolytic metabolism were evaluated in nonactivated murine peritoneal macrophages (MΦ₀) and macrophages stimulated with M-CSF (MΦ_M-CSF) or GM-CSF (MΦ_GM-CSF). Intracellular glucose flux was measured by using stable isotope tracing of glycolytic and tricyclic acid intermediary metabolites. ¹⁸F-FDG uptake was evaluated in murine atherosclerotic aortas after stimulation with M-CSF or GM-CSF by using quantitative autoradiography. Results: Despite inducing distinct activation states, GM-CSF and M-CSF stimulated progressive but similar levels of increased 2-deoxyglucose uptake in macrophages that reached up to sixfold compared with MΦ₀. The expression of glucose transporters, oxidative metabolism, and mitochondrial biogenesis were induced to similar levels in MΦ_M-CSF and MΦ_GM-CSF. Unexpectedly, there was a 1.7-fold increase in extracellular acidification rate, a 1.4-fold increase in lactate production, and overexpression of several critical glycolytic enzymes in MΦ_M-CSF compared with MΦ_GM-CSF with associated increased glucose flux through glycolytic pathway. Quantitative autoradiography demonstrated a 1.6-fold induction of ¹⁸F-FDG uptake in murine atherosclerotic plaques by both M-CSF and GM-CSF. Conclusion: The proinflammatory and inflammation-resolving activation states of macrophages induced by GM-CSF and M-CSF in either cell culture or atherosclerotic plaques may not be distinguishable by the assessment of glucose uptake.