Pharmacological and Genetic Targeting of Inflammatory Chemokine Receptors CCR1, CCR2, and CCR5 in Atherosclerosis: A Systematic Review and Meta‐Analysis of Preclinical Studies

BACKGROUND: Inflammatory chemokine receptors encompassing CCR1, CCR2, CCR3, and CCR5 orchestrate the recruitment of leukocytes during inflammation. In atherosclerosis, there is ongoing controversy surrounding the precise role each inflammatory chemokine receptor plays in the disease process. We thus performed a systematic review and meta-analysis to examine the effects of inflammatory chemokine receptor inhibition on experimental atherosclerotic burden. METHODS: We performed a systematic literature search of PubMed/MEDLINE, Embase, and Web of Science for studies on the pharmacological and/or genetic manipulation of inflammatory chemokine receptors in murine models of atherosclerosis or hyperlipidemia. We extracted data on lesion size and morphological composition as primary outcomes, and plasma lipid profile and mouse body weight as secondary outcomes. We used a random effects model to calculate the pooled effect size across studies as the standardized mean difference (SMD) with 95% CIs. RESULTS: A total of 38 studies of experimental atherosclerosis (CCR1: n=9, CCR2: n=24, CCR5: n=13) were included. Genetic or pharmacological inhibition of CCR2 and CCR5 significantly reduced lesion size (CCR2: SMD=-1.14 [95% CI, -1.47 to -0.81]; CCR5: SMD=-1.06 [95% CI, -1.64 to -0.48]), (CCR2: SMD=-0.72 [95% CI, -1.15 to -0.29]; CCR5: SMD=-1.92 [95% CI, -2.58 to -1.26]) and macrophage load (CCR2: SMD=-1.35 [95% CI, -1.97 to -0.74], CCR5: SMD=-1.29 [95% CI, -2.39 to -0.20]), (CCR2: SMD=-0.86 [95% CI, -1.43 to -0.29]; CCR5: SMD=-1.69 [95% CI, -2.69 to -0.69]), respectively. Pharmacological (but not genetic) targeting of CCR1 significantly reduced lesion size, with protection observed only in males when both approaches were considered. CONCLUSIONS: Our analysis suggests that inhibition of either CCR2 or CCR5 is protective in experimental atherosclerosis, while the effect of CCR1 intervention is less clear with potential beneficial effects in male populations.