Metabolic Disease Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Japan.
J Nucl Med. 2013 Jun;54(6):999-1004. doi: 10.2967/jnumed.112.110551. Epub 2013 May 13.
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.
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.
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.
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.
评估动脉粥样硬化斑块的方法有很多，包括各种非侵入性成像技术。其中，（18）F-FDG PET 和超顺磁性氧化铁颗粒（USPIO）的磁共振成像已被用于定量评估斑块炎症。这两种方法都是基于 FDG 和 USPIO 被动脉粥样硬化病变中的巨噬细胞高效摄取。据报道，极化状态不同的巨噬细胞具有不同的特征，这些特征与动脉粥样硬化的病理发展有关。M1 极化的巨噬细胞被认为比 M2 极化的巨噬细胞更具促动脉粥样硬化表型。然而，对于巨噬细胞极化与 FDG 或 USPIO 积聚之间的关系，我们知之甚少。在这项研究中，我们研究了 M1 和 M2 极化的巨噬细胞内的 FDG 和 USPIO 积聚。
将 THP-1 巨噬细胞分化为 M1 和 M2 极化的巨噬细胞。在最佳葡萄糖条件下，我们研究了 M1 和 M2 极化的巨噬细胞对（3）H 标记的 FDG 的摄取。然后，我们研究了 M1 和 M2 巨噬细胞内的 USPIO 摄取。
我们发现，与 M2 极化相比，M1 极化导致 FDG 在内化中的积累增加。为了阐明 FDG 优先在 M1 巨噬细胞中积累的机制，我们检测了葡萄糖转运体（GLUTs）和己糖激酶的信使 RNA 表达，它们在葡萄糖摄取中起关键作用，以及葡萄糖-6-磷酸酶（G6Pase），它催化己糖激酶的逆反应。在 M1 巨噬细胞中，GLUT-1、GLUT-3、己糖激酶 1 和己糖激酶 2 上调，G6Pase 下调。与 FDG 相反，M1 极化导致 USPIO 在内化中的积累减少。我们发现，参与 USPIO 结合和摄取的清道夫受体 A 和 CD11b 显著下调。
与 M2 相比，促动脉粥样硬化的 M1 巨噬细胞优先积累 FDG 而不是 USPIO，这表明 FDG PET 是检测促炎 M1 巨噬细胞的一种有用方法。
