title: Differential Regulation of Macrophage Glucose Metabolism by Macrophage Colony-stimulating Factor and Granulocyte-Macrophage Colony-stimulating Factor: Implications for18F FDG PET Imaging of Vessel Wall Inflammation.
abstract: Purpose To determine the divergence of immunometabolic phenotypes of macrophages stimulated with macrophage colony-stimulating factor (M-CSF) 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 (MΦM-CSF) or GM-CSF (MΦGM-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 MΦM-CSFand MΦGM-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 MΦM-CSFcompared with MΦGM-CSFwith associated increased glucose flux through glycolytic pathway. Quantitative autoradiography demonstrated a 1.6-fold induction of18F-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.©RSNA, 2016 Online supplemental material is available for this article.
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Sina
authors.initials: S
authors.lastname: Tavakoli
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: John D
authors.initials: JD
authors.lastname: Short
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Downs
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Huynh Nga
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Yanlai
authors.initials: Y
authors.lastname: Lai
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Paul
authors.initials: P
authors.lastname: Jerabek
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Beth
authors.initials: B
authors.lastname: Goins
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Mehran M
authors.initials: MM
authors.lastname: Sadeghi
authors.affiliation: From the Departments of Radiology (S.T., P.J., B.G., R.A.), Pharmacology (J.D.S.), Cellular and Structural Biology (K.D.), Biochemistry (H.N.N., R.A.), and Clinical Laboratory Sciences (Y.L., R.A.) and Research Imaging Institute (W.Z., P.J.), University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, MC-8254, San Antonio, TX 78229-3904; and Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Conn (M.M.S.).
authors.forename: Reto
authors.initials: R
authors.lastname: Asmis
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007249:Inflammation / Q000000981:diagnostic imaging* / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005947:Glucose