title: Comparison of contrast agents for atherosclerosis imaging using cultured macrophages: FDG versus ultrasmall superparamagnetic iron oxide.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Metabolic Disease Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Japan. tomoko.satomi@takeda.com
authors.forename: Tomoko
authors.initials: T
authors.lastname: Satomi
authors.forename: Mikako
authors.initials: M
authors.lastname: Ogawa
authors.forename: Ikuo
authors.initials: I
authors.lastname: Mori
authors.forename: Seigo
authors.initials: S
authors.lastname: Ishino
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kubo
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Magata
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishimoto
mesh_terms: D050197:Atherosclerosis / Q000175:diagnosis*; D001692:Biological Transport; D002460:Cell Line; D002478:Cells, Cultured; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry* / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D059346:Magnets / Q000737:chemistry; D057054:Molecular Imaging / Q000379:methods*; D010316:Particle Size
chemical_list: D003287:Contrast Media; D005290:Ferric Compounds; D019788:Fluorodeoxyglucose F18; C000499:ferric oxide; D005947:Glucose
keywords: FDG; USPIO; atherosclerosis; macrophage; polarization