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Differential Regulation of Macrophage Glucose Metabolism by M‐CSF and GM‐CSF: Implications for 18 F‐FDG PET Imaging of Inflammation
Author(s) -
Tavakoli Sina,
Short John D,
Downs Kevin,
Nga Nguyen Huynh,
Asmis Reto
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.57.8
Subject(s) - granulocyte macrophage colony stimulating factor , inflammation , mitochondrial biogenesis , glycolysis , glucose transporter , glucose uptake , macrophage , glut1 , macrophage colony stimulating factor , biology , carbohydrate metabolism , deoxyglucose , cytokine , metabolism , chemistry , endocrinology , biochemistry , mitochondrion , immunology , insulin , in vitro
Background The high glycolytic capacity of macrophages allows for the utilization of 18 F‐FDG in the detection of inflammation associated with various diseases. Microenvironmental signals (such as growth factors, cytokines and pathogen‐derived products) have profound effects on determining the activation state of macrophages, which in turn is delicately regulated through reprogramming of cell metabolism. Specifically, glycolysis has been suggested to enhance the pro‐inflammatory macrophage phenotype induced by pathogen‐derived stimuli. Here, we examined whether this phenomenon extends to endogenous microenvironmental activators by investigating the metabolic effects of two critical myeloid growth factors with opposing effects on the macrophage inflammatory state, i.e., macrophage colony‐stimulating factor (M‐CSF) and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Methods Murine peritoneal macrophages (Mϕ) were incubated ex vivo for two days in the absence (Mϕ 0 ) or presence of M‐CSF (Mϕ M‐CSF ) or GM‐CSF (Mϕ GM‐CSF ). Glucose uptake was measured using 3 H‐2‐deoxyglucose. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), markers of oxidative and glycolytic metabolism, as well as mitochondrial content of the cells and lactate production were quantified. Expression of activation markers, glucose transporters and metabolic enzymes was measured by high‐throughput quantitative reverse‐transcription PCR. Results M‐CSF and GM‐CSF stimulated comparable levels of 3 H‐2‐deoxyglucose uptake and induced similar expression levels of glucose transporter‐1 and ‐6 in Mϕ. Similarly, mitochondrial biogenesis and oxidative metabolism were induced to the same levels in Mϕ M‐CSF and Mϕ GM‐CSF . Unexpectedly, activation of glycolysis was more pronounced in Mϕ M‐CSF compared to Mϕ GM‐CSF , as evidenced by higher basal ECAR and ECAR‐to‐OCR ratio, as well as lactate production. A number of critical glycolytic enzymes were also differentially upregulated in Mϕ M‐CSF compared to Mϕ GM‐CSF . Conclusion Despite their pro‐inflammatory activation state, Mϕ GM‐CSF showed the same level of glucose uptake and oxidative metabolism as Mϕ M‐CSF , which are associated with inflammation resolution. Furthermore, Mϕ M‐CSF , not the pro‐inflammatory Mϕ GM‐CSF , demonstrate the higher glycolytic activity. These findings strongly suggest that the reported association between a pro‐inflammatory macrophage phenotype and increased glucose uptake and glycolysis is limited to certain microenvironmental signals, and does not represent a universal phenomenon, calling for a more prudent approach in the interpretation of 18 F‐FDG imaging of inflammation. Support or Funding Information This work was supported by grants from Radiological Society of North America Grant to S.T. (RR1131) and the National Institute of Health (HL115858) to R.A.