Pharmacological Targeting of the CCL2/CCR2 Axis for Atheroprotection: A Meta-Analysis of Preclinical Studies

Abstract

Background: 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. Methods: 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. Results: In a meta-analysis of 14 studies testing 11 different agents, CCL2/CCR2 blockade attenuated atherosclerotic lesion size in the aortic root or arch ( g =−0.75 [−1.17 to −0.32], P =6×10 − 4 ; N=171/171 mice in experimental/control group), the carotid ( g =−2.39 [−4.23 to −0.55], P =0.01; N=24/25), and the femoral artery ( g =−2.38 [−3.50 to −1.26], P =3×10 − 5 ; 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. Conclusions: 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.