Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart
Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart
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DOI：
10.1161/circresaha.118.314030
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发表时间：
2019-03-15
影响因子：
20.1
通讯作者：
Lavine, Kory J.
中科院分区：
文献类型：
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作者：
Heo, Gyu Seong;Kopecky, Benjamin;Lavine, Kory J.
理由：范式转变研究表明，心脏含有功能多样的巨噬细胞群，这些巨噬细胞群源自不同的胚胎和成人造血祖细胞。在稳态条件下，心脏主要由胚胎血统的 CCR2-（C-C 趋化因子受体 2 型）巨噬细胞占据。组织损伤后，巨噬细胞组成发生显着变化，CCR2+单核细胞被募集到心脏并分化为炎症性CCR2+巨噬细胞，从而导致心力衰竭进展。目前，还没有技术可以无创地检测 CCR2+ 单核细胞募集到心脏中，从而识别可能适合免疫调节治疗的患者。 目的：开发一种具有高灵敏度和特异性的无创分子成像策略，以可视化心脏中炎症单核细胞和巨噬细胞的聚集。 方法和结果：我们合成并测试了正电子发射断层扫描放射性示踪剂（Ga-68-DOTA [ 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸]-ECL1i [细胞外环 1 inverso]）以变构方式与 CCR2 结合。在首次实验的小鼠中，放射性示踪剂很快从血液中清除，并在主要器官中显示出极少的滞留。相比之下，生物分布和正电子发射断层扫描表明，在两种心脏损伤模型（白喉毒素诱导的心肌细胞消融和再灌注心肌梗死）中，心肌示踪剂的摄取较强。 Ga-68-DOTA-ECL1i 信号定位于组织损伤部位，并且通过定量正电子发射断层扫描和离体放射自显影评估，与血池活性无关。 Ga-68-DOTA-ECL1i 摄取与 CCR2+ 单核细胞和 CCR2+ 巨噬细胞浸润心脏相关，但在 CCR2(-/-) 小鼠中被消除，证明了靶标特异性。放射自显影证明 Ga-68-DOTA-ECL1i 特异性结合人类心力衰竭标本，且信号强度与 CCR2+ 巨噬细胞丰度相关。结论：这些发现证明了 Ga-68-DOTA-ECL1i 在小鼠心脏中的敏感性和特异性，并强调了该药物在患者中无创可视化 CCR2+ 单核细胞募集和炎症巨噬细胞积聚的转化潜力。
Rationale: Paradigm shifting studies have revealed that the heart contains functionally diverse populations of macrophages derived from distinct embryonic and adult hematopoietic progenitors. Under steady-state conditions, the heart is largely populated by CCR2-(C-C chemokine receptor type 2) macrophages of embryonic descent. After tissue injury, a dramatic shift in macrophage composition occurs whereby CCR2+ monocytes are recruited to the heart and differentiate into inflammatory CCR2+ macrophages that contribute to heart failure progression. Currently, there are no techniques to noninvasively detect CCR2+ monocyte recruitment into the heart and thus identify patients who may be candidates for immunomodulatory therapy.Objective: To develop a noninvasive molecular imaging strategy with high sensitivity and specificity to visualize inflammatory monocyte and macrophage accumulation in the heart.Methods and Results: We synthesized and tested the performance of a positron emission tomography radiotracer (Ga-68-DOTA [ 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ECL1i [ extracellular loop 1 inverso]) that allosterically binds to CCR2. In naive mice, the radiotracer was quickly cleared from the blood and displayed minimal retention in major organs. In contrast, biodistribution and positron emission tomography demonstrated strong myocardial tracer uptake in 2 models of cardiac injury (diphtheria toxin induced cardiomyocyte ablation and reperfused myocardial infarction). Ga-68-DOTA-ECL1i signal localized to sites of tissue injury and was independent of blood pool activity as assessed by quantitative positron emission tomography and ex vivo autoradiography. Ga-68-DOTA-ECL1i uptake was associated with CCR2+ monocyte and CCR2+ macrophage infiltration into the heart and was abrogated in CCR2(-/-) mice, demonstrating target specificity. Autoradiography demonstrated that Ga-68-DOTA-ECL1i specifically binds human heart failure specimens and with signal intensity associated with CCR2+ macrophage abundance.Conclusions: These findings demonstrate the sensitivity and specificity of Ga-68-DOTA-ECL1i in the mouse heart and highlight the translational potential of this agent to noninvasively visualize CCR2+ monocyte recruitment and inflammatory macrophage accumulation in patients.