Živković Luka, Asare Yaw, Bernhagen Jürgen, Dichgans Martin, Georgakis Marios K
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Germany (L.Ž., Y.A., J.B., M.D., M.K.G.).
Munich Cluster for Systems Neurology (SyNergy), Germany (J.B., M.D.).
Arterioscler Thromb Vasc Biol. 2022 May;42(5):e131-e144. doi: 10.1161/ATVBAHA.122.317492. Epub 2022 Apr 7.
The CCL2 (CC-chemokine ligand 2)/CCR2 (CC-chemokine receptor 2) axis governs monocyte recruitment to atherosclerotic lesions. Genetic and epidemiological studies show strong associations of CCL2 levels with atherosclerotic disease. Still, experimental studies testing pharmacological inhibition of CCL2 or CCR2 in atheroprone mice apply widely different approaches and report variable results, thus halting clinical translation.
We systematically searched the literature for studies employing pharmacological CCL2/CCR2 blockade in atheroprone mice and meta-analyzed their effects on lesion size and morphology.
In a meta-analysis of 14 studies testing 11 different agents, CCL2/CCR2 blockade attenuated atherosclerotic lesion size in the aortic root or arch (=-0.75 [-1.17 to -0.32], =6×10; N=171/171 mice in experimental/control group), the carotid (=-2.39 [-4.23 to -0.55], =0.01; N=24/25), and the femoral artery (=-2.38 [-3.50 to -1.26], =3×10; N=10/10). Furthermore, CCL2/CCR2 inhibition reduced intralesional macrophage accumulation and increased smooth muscle cell content and collagen deposition. The effects of CCL2/CCR2 inhibition on lesion size correlated with reductions in plaque macrophage accumulation, in accord with a prominent role of CCL2/CCR2 signaling in monocyte recruitment. Subgroup analyses showed comparable efficacy of different CCL2- and CCR2-inhibitors in reducing lesion size and intralesional macrophages. The quality assessment revealed high risk of detection bias due to lack of blinding during outcome assessment, as well as evidence of attrition and reporting bias.
Preclinical evidence suggests that pharmacological targeting of CCL2 or CCR2 might lower atherosclerotic lesion burden, but the majority of existing studies suffer major quality issues that highlight the need for additional high-quality research.
CCL2（CC趋化因子配体2）/CCR2（CC趋化因子受体2）轴调控单核细胞向动脉粥样硬化病变部位的募集。遗传和流行病学研究表明CCL2水平与动脉粥样硬化疾病密切相关。然而，在易患动脉粥样硬化的小鼠中测试CCL2或CCR2的药理学抑制作用的实验研究采用了广泛不同的方法，并且报告的结果各异，从而阻碍了临床转化。
我们系统检索了在易患动脉粥样硬化的小鼠中采用药理学CCL2/CCR2阻断的研究文献，并对其对病变大小和形态的影响进行了荟萃分析。
在对测试11种不同药物的14项研究进行的荟萃分析中，CCL2/CCR2阻断减轻了主动脉根部或弓部的动脉粥样硬化病变大小（标准化均数差=-0.75 [-1.17至-0.32]，P=6×10⁻⁶；实验组/对照组中N=171/171只小鼠）、颈动脉（标准化均数差=-2.39 [-4.23至-0.55]，P=0.01；N=24/25）和股动脉（标准化均数差=-2.38 [-3.50至-1.26]，P=3×10⁻⁴；N=10/10）的病变大小。此外，CCL2/CCR2抑制减少了病变内巨噬细胞的积聚，并增加了平滑肌细胞含量和胶原沉积。CCL2/CCR2抑制对病变大小的影响与斑块巨噬细胞积聚的减少相关，这与CCL2/CCR2信号在单核细胞募集中的重要作用一致。亚组分析显示不同的CCL2和CCR2抑制剂在减少病变大小和病变内巨噬细胞方面具有相当的疗效。质量评估显示，由于结局评估期间缺乏盲法，存在较高的检测偏倚风险，以及失访和报告偏倚的证据。
临床前证据表明，对CCL2或CCR2进行药理学靶向可能会降低动脉粥样硬化病变负担，但大多数现有研究存在重大质量问题，这突出表明需要进行更多高质量的研究。
