Characterization of Macrophage Polarization States Using Combined Measurement of 2-Deoxyglucose and Glutamine Accumulation: Implications for Imaging of Atherosclerosis.
Characterization of Macrophage Polarization States Using Combined Measurement of 2-Deoxyglucose and Glutamine Accumulation: Implications for Imaging of Atherosclerosis.
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DOI：
10.1161/atvbaha.117.308848
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Asmis R
中科院分区：
文献类型：
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作者：
Tavakoli S;Downs K;Short JD;Nguyen HN;Lai Y;Jerabek PA;Goins B;Toczek J;Sadeghi MM;Asmis R
尽管18F-氟代脱氧葡萄糖正电子发射断层扫描在评估血管壁炎方面取得了良好的早期结果，但它在预测易损斑块方面的准确性仍然有限。此外，以前的研究表明，单独摄取18F-氟代脱氧葡萄糖可能不足以准确识别特定的巨噬细胞激活状态。我们的目标是确定联合测量葡萄糖和谷氨酰胺积累-巨噬细胞最重要的两种生物能量底物-是否可以改善巨噬细胞炎症状态的区分，并可用于成像动脉粥样硬化。用脂多糖(MΦ)或干扰素-γ+肿瘤坏死因子-α(M-Φ-γ+α)体外激活小鼠腹膜巨噬细胞(M-CFM)，使其处于促炎状态。用白细胞介素4(MΦIL 4)诱导另一种极化表型。MΦ内毒素对2-脱氧葡萄糖摄取的显著增加区别于MΦ干扰素-γ+肿瘤坏死因子-α、MΦIL-4和未刺激的巨噬细胞(MΦ0)。尽管M-ΦIL-4具有相似的2-脱氧葡萄糖积累水平，但基于谷氨酰胺积累的增加，M-ΦIL-4可以与M-γ干扰素-α+肿瘤坏死因子-Φ和M-GFP-0区分开来，这与谷氨酰胺转运体SLC1a5的表达增加有关。体外放射自显影实验表明，在高脂饮食喂养的低密度脂蛋白受体缺失小鼠的动脉粥样硬化病变中，18F-脱氧葡萄糖和14C-谷氨酰胺的积聚具有明显的异质性。联合评估谷氨酰胺和2-脱氧葡萄糖蓄积可改善巨噬细胞激活状态的体外鉴定。联合体外代谢成像显示动脉粥样硬化病变中不同的和不同的底物积聚模式。需要进一步的研究来确定谷氨酰胺摄取在动脉粥样硬化中的体内意义以及它在识别易损斑块方面的潜在应用。
Despite the early promising results of 18F-fluorodeoxyglucose positron emission tomography for assessment of vessel wall inflammation, its accuracy in prospective identification of vulnerable plaques has remained limited. Additionally, previous studies have indicated that 18F-fluorodeoxyglucose uptake alone may not allow for accurate identification of specific macrophage activation states. We aimed to determine whether combined measurement of glucose and glutamine accumulation—the 2 most important bioenergetic substrates for macrophages—improves the distinction of macrophage inflammatory states and can be utilized to image atherosclerosis. Murine peritoneal macrophages (MΦ) were activated ex vivo into proinflammatory states with either lipopolysaccharide (MΦLPS) or interferon-γ+tumor necrosis factor-α (MΦIFN-γ+TNF-α). An alternative polarization phenotype was induced with interleukin-4 (MΦIL-4). The pronounced increase in 2-deoxyglucose uptake distinguishes MΦLPS from MΦIFN-γ+TNF-α, MΦIL-4, and unstimulated macrophages (MΦ0). Despite having comparable levels of 2-deoxyglucose accumulation, MΦIL-4 can be distinguished from both MΦIFN-γ+TNF-α and MΦ0 based on the enhanced glutamine accumulation, which was associated with increased expression of a glutamine transporter, Slc1a5. Ex vivo autoradiography experiments demonstrated distinct and heterogenous patterns of 18F-fluorodeoxyglucose and 14C-glutamine accumulation in atherosclerotic lesions of low-density lipoprotein receptor-null mice fed a high-fat diet. Combined assessment of glutamine and 2-deoxyglucose accumulation improves the ex vivo identification of macrophage activation states. Combined ex vivo metabolic imaging demonstrates heterogenous and distinct patterns of substrate accumulation in atherosclerotic lesions. Further studies are required to define the in vivo significance of glutamine uptake in atherosclerosis and its potential application in identification of vulnerable plaques.