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

Sina Tavakoli; John D. Short; Kevin Downs; Huynh Nga Nguyen; Yanlai Lai; Wei Zhang; Paul Jerabek; Beth Goins; Mehran M. Sadeghi; Reto Asmis

doi:10.1148/radiol.2016160839

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

Sina Tavakoli, John D. Short, Kevin Downs, Huynh Nga Nguyen, Yanlai Lai, Wei Zhang, Paul Jerabek, Beth Goins, Mehran M. Sadeghi, Reto Asmis

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	87-97
Number of pages	11
Journal	Radiology
Volume	283
Issue number	1
DOIs	https://doi.org/10.1148/radiol.2016160839
State	Published - Apr 2017

ASJC Scopus subject areas

Radiology Nuclear Medicine and imaging

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10.1148/radiol.2016160839

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Tavakoli, S., Short, J. D., Downs, K., Nguyen, H. N., Lai, Y., Zhang, W., Jerabek, P., Goins, B., Sadeghi, M. M., & Asmis, R. (2017). 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. Radiology, 283(1), 87-97. https://doi.org/10.1148/radiol.2016160839

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. / Tavakoli, Sina; Short, John D.; Downs, Kevin; Nguyen, Huynh Nga; Lai, Yanlai; Zhang, Wei; Jerabek, Paul ; Goins, Beth; Sadeghi, Mehran M.; Asmis, Reto.

In: Radiology, Vol. 283, No. 1, 04.2017, p. 87-97.

Research output: Contribution to journal › Article › peer-review

Tavakoli, S, Short, JD, Downs, K, Nguyen, HN, Lai, Y, Zhang, W, Jerabek, P , Goins, B, Sadeghi, MM & Asmis, R 2017, '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', Radiology, vol. 283, no. 1, pp. 87-97. https://doi.org/10.1148/radiol.2016160839

Tavakoli, Sina ; Short, John D. ; Downs, Kevin ; Nguyen, Huynh Nga ; Lai, Yanlai ; Zhang, Wei ; Jerabek, Paul ; Goins, Beth ; Sadeghi, Mehran M. ; Asmis, Reto. / 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. In: Radiology. 2017 ; Vol. 283, No. 1. pp. 87-97.

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title = "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",

abstract = "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 (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-CSF and 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-CSF compared with MΦGM-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.",

author = "Sina Tavakoli and Short, {John D.} and Kevin Downs and Nguyen, {Huynh Nga} and Yanlai Lai and Wei Zhang and Paul Jerabek and Beth Goins and Sadeghi, {Mehran M.} and Reto Asmis",

note = "Funding Information: High-throughput gene expression data were generated in the Core for Advanced Translational Technologies, University of Texas Health Science Center at San Antonio. Joe Cuellar kindly assisted in preparation of the gene expression methodologic analysis. We appreciate Dr Nicolas Musi's support with Extracellular Flux Analyzer experiments, performed at Healthspan and Functional Assessment Core supported by Nathan Shock Center for Excellence in Basic Biology of Aging Grant (AG13319). Flow cytometry data were generated in the Flow Cytometry Shared Resource Facility, supported by University of Texas Health Science Center at San Antonio, NIH-NCI P30 CA054174-20 and UL1 TR001120 grants. 13C-labeled glucose flux analysis was performed utilizing Metabolomics Core Services supported by grant U24 DK097153 of NIH Common Funds Project to the University of Michigan. Publisher Copyright: {\textcopyright} 2017 RSNA.",

year = "2017",

month = apr,

doi = "10.1148/radiol.2016160839",

language = "English (US)",

volume = "283",

pages = "87--97",

journal = "Radiology",

issn = "0033-8419",

publisher = "Radiological Society of North America Inc.",

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TY - JOUR

T1 - Differential regulation of macrophage glucose metabolism by macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor

T2 - Implications for 18F FDG PET imaging of vessel wall inflammation

AU - Tavakoli, Sina

AU - Short, John D.

AU - Downs, Kevin

AU - Nguyen, Huynh Nga

AU - Lai, Yanlai

AU - Zhang, Wei

AU - Jerabek, Paul

AU - Goins, Beth

AU - Sadeghi, Mehran M.

AU - Asmis, Reto

N1 - Funding Information: High-throughput gene expression data were generated in the Core for Advanced Translational Technologies, University of Texas Health Science Center at San Antonio. Joe Cuellar kindly assisted in preparation of the gene expression methodologic analysis. We appreciate Dr Nicolas Musi's support with Extracellular Flux Analyzer experiments, performed at Healthspan and Functional Assessment Core supported by Nathan Shock Center for Excellence in Basic Biology of Aging Grant (AG13319). Flow cytometry data were generated in the Flow Cytometry Shared Resource Facility, supported by University of Texas Health Science Center at San Antonio, NIH-NCI P30 CA054174-20 and UL1 TR001120 grants. 13C-labeled glucose flux analysis was performed utilizing Metabolomics Core Services supported by grant U24 DK097153 of NIH Common Funds Project to the University of Michigan. Publisher Copyright: © 2017 RSNA.

PY - 2017/4

Y1 - 2017/4

N2 - 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 (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-CSF and 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-CSF compared with MΦGM-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.

AB - 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 (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-CSF and 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-CSF compared with MΦGM-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.

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