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Published on: October 20, 2013
Comparison of contrast agents for atherosclerosis imaging using cultured macrophages: FDG versus ultrasmall
Tomoko Satomi1, Mikako Ogawa, Ikuo Mori
1Metabolic Disease Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Japan. tomoko.satomi@takeda.com
Unlabelled:
Various noninvasive imaging methods have been developed to evaluate atherosclerotic plaques. Among them, (18)F-FDG PET and MR imaging with ultrasmall superparamagnetic iron oxide particles (USPIO) have been used to quantify plaque inflammation. Both methods are based on the efficient uptake of FDG and USPIO by macrophages in atherosclerotic lesions. Differently polarized macrophages have been reported to have different characteristics that are involved in the pathologic development of atherosclerosis. M1 polarized macrophages are considered the more proatherogenic phenotype than M2 polarized macrophages. However, little is known regarding the association between macrophage polarization and FDG or USPIO accumulation. In this study, we investigated intracellular FDG and USPIO accumulation in M1 and M2 polarized macrophages.
Methods:
THP-1 macrophages were differentiated into M1 and M2 polarized macrophages. Under optimal glucose conditions, we investigated the (3)H-labeled FDG uptake in M1 and M2 polarized macrophages. We then investigated intracellular USPIO uptake by M1 and M2 macrophages.
Results:
We found that M1 polarization, compared with M2 polarization, results in increased intracellular accumulation of FDG. To elucidate the mechanism by which FDG was preferentially accumulated in M1 macrophages, we examined messenger RNA expressions of glucose transporters (GLUTs) and hexokinases, which have pivotal roles in glucose uptake, and glucose-6-phosphatase (G6Pase), which catalyzes the reverse reaction of hexokinase. In M1 macrophages, GLUT-1, GLUT-3, hexokinase 1, and hexokinase 2 were upregulated and G6Pase was downregulated. In contrast to FDG, M1 polarization resulted in decreased intracellular accumulation of USPIO. We found that scavenger receptor A and CD11b, which are involved in USPIO binding and uptake, were significantly downregulated by M1 polarization.
Conclusion:
Compared with M2, proatherogenic M1 macrophages preferentially accumulated FDG but not USPIO, suggesting that FDG PET is a useful method for the detection of proinflammatory M1 macrophages.
Insights
Pro-atherogenic M1 macrophages accumulate more (18)F-FDG PET tracer than M2 macrophages, but not ultrasmall superparamagnetic iron oxide particles (USPIO). This suggests (18)F-FDG PET can detect M1 macrophages in atherosclerotic plaques.
Area of Science:
- Cardiovascular Imaging
- Immunology
- Molecular Imaging
Background:
- Noninvasive imaging methods like (18)F-FDG PET and USPIO-enhanced MRI evaluate atherosclerotic plaques by targeting macrophage uptake.
- Macrophages exhibit different polarization states (M1 and M2) with distinct roles in atherosclerosis pathogenesis.
- The association between macrophage polarization and tracer accumulation (FDG or USPIO) remains unclear.
Purpose of the Study:
- To investigate the differential intracellular accumulation of (18)F-FDG and USPIO in M1 versus M2 polarized macrophages.
- To explore the underlying mechanisms of tracer uptake related to macrophage polarization.
Main Methods:
- THP-1 macrophages were differentiated into M1 and M2 phenotypes.
- Uptake of (3)H-labeled (18)F-FDG was measured under optimal glucose conditions.
- Intracellular USPIO uptake was assessed in both M1 and M2 macrophages.
Main Results:
- M1 macrophages showed significantly higher intracellular (18)F-FDG accumulation compared to M2 macrophages.
- Upregulation of GLUT-1, GLUT-3, hexokinase 1, and hexokinase 2, with downregulation of G6Pase, was observed in M1 macrophages.
- (18)F-FDG accumulation in M1 macrophages is linked to enhanced glucose metabolism.
- Conversely, M1 polarization led to decreased intracellular USPIO accumulation.
- Scavenger receptor A and CD11b, involved in USPIO uptake, were downregulated in M1 macrophages.
Conclusions:
- Pro-atherogenic M1 macrophages preferentially accumulate (18)F-FDG, but not USPIO, compared to M2 macrophages.
- (18)F-FDG PET imaging may serve as a valuable tool for detecting proinflammatory M1 macrophages in atherosclerosis.
