Genetic Deletion of CCRL2 Impairs Macrophage Accumulation in Arterial Intima and Attenuates Atherosclerotic Plaque Development

Atherosclerosis is a chronic inflammatory disease of the arterial wall elicited by accumulation of LDL and leucocytes in the subendothelium at predilection sites with disturbed laminar flow. Chemokines and their receptors appear to act as critical players in atherosclerosis as they not only direct atherogenic recruitment of leucocytes but also exert cell hemostatic functions by chemokine ligand-receptor axes and their specific or combined contributions. Chemokine (C-C motif) receptor-like 2 (CCRL2) is an atypical chemokine receptor that cooperates with its ligand chemerin to play a role in cell trafficking and inflammatory response, the processes usually occur in atherosclerosis, but its role in atherosclerosis is not clear. Here we investigated the potential role of CCRL2 in atherogenesis using the classic apolipoprotein E-deficient (ApoE-/-) mouse model of atherosclerosis. Atherosclerosis-prone ApoE-/- mice were crossed with CCRL2-/- mice to obtain ApoE-/-CCRL2+/+ and ApoE-/-CCRL2-/- mice. Male mice of both genotypes were fed a standard chow diet until 8 weeks of age and then switched to a high fat diet for 16 weeks. Aortas were dissected and assessed by en face staining. Although CCRL2 deletion did not change mouse blood lipid profile and body weight, the atherosclerotic plaque area of the total aorta was reduced by 27.2% (P=0.0379) in ApoE-/-CCRL2-/- mice compared with ApoE-/-CCRL2+/+ mice with striking difference occurring in aortic arch. A reduction of lipid deposition by 32.6% (P=0.0089) was also observed in aortic root sections when CCRL2 was deleted. Further studies showed that deletion of CCRL2 reduced macrophage accumulation and polarization during the development of atherosclerosis. CCRL2 not only expresses in high levels in the plaques of ApoE-/- mice on a high fat diet but also co-localizes with macrophages and chemerin. Interestingly, using CMKLR1-/- chimeric mice, we showed that chemerin/CMKLR1/CCRL2 axis is involved in leucocyte infiltration and possibly affects plaque formation. More importantly, partial carotid artery ligation (PCL) model confirmed that disturbed blood flow-induced endothelial expression of CCRL2 modulates plaque formation. In conclusion, our results demonstrate that CCRL2 deficiency delays macrophage accumulation and the formation of atherosclerotic plaques potentially via the disruption of chemerin/CMKLR1/CCRL2 axis and the loss of CCRL2 response to the disturbed flow, which may represent a novel mechanism of atherosclerosis. This work was supported by Natural Science Foundation of China (grant 81370373 to L.Z. and 31300781 to C.T.)