Table 2.

The roles of key chemokine receptors in atherosclerosis.

Receptor	Summary of studies using mouse model systems	Ref.
CCR1	Deficiency in the ApoE−/− model increases plaque area, T-cell content and levels of IFN-γ but doesn’t protect against neointima formation following wire injury.	[43], [44]
CCR2	Deficiency in the ApoE−/− model reduces lesion formation. Transplantation of CCR2 deficient bone marrow in the ApoE−/− model suppresses angiotensin II-mediated acceleration of atherosclerosis and abdominal aortic aneurysm, and in the ApoE3-Leiden model reduces overall atherosclerotic lesion development but has no effect on the progression of established plaques. Pharmacological inhibition reduces macrophage infiltration in the ApoE−/− model expressing human CCR2. Monocyte-targeted RNA interference in the ApoE−/− model reduces recruitment of Ly-6Chigh monocytes, attenuates inflammation and improves infarct healing.	[22], [45], [46], [47], [48], [49], [50]
CCR5	Deficiency in the ApoE−/− model protects against atherosclerosis and is associated with a more stable plaque phenotype, reduced infiltration of monocytes and decreased Th1 inflammatory response, and increased production of IL-10. An important role in late-stage atherosclerosis was also identified involving modulation of macrophage accumulation in the plaque and reduction in circulating levels of IL-6 and MCP-5. Antagonist attenuates atherosclerosis and reduces myocardial reperfusion injury in mouse models. Transplantation of CCR5 deficient bone marrow in the LDLr−/− model attenuates atherosclerosis with increased IL-10 expression and reduced TNF-α levels.	[43], [51], [52], [53], [54]
CCR6	Deficiency in the LDLr−/− model reduces atherosclerotic burden by affecting monocyte-mediated inflammation. Reduced atherosclerosis also seen in the ApoE−/− model accompanied by decrease in both circulating levels of monocytes and their migration. BMT reveals importance of chemokine expressed by hematopoietic cells.	[55], [56]
CCR7	Expression induced in an atherosclerosis regression model in ApoE−/− mice. Abrogation of function using antibodies against ligands CCL19 and CCL21 preserved lesion size and foam cell content in this model. Deficiency in the LDLr−/− model attenuates atherosclerosis by modulating T-cell entry and exit into lesions. In contrast, deficiency in the ApoE−/− model exacerbates the disease by increasing T-cell accumulation. BMT confirms the importance of CCR7 expressed by hematopoietic cells.	[57], [58], [59]
CXCR2	Transplantation of CXCR2 deficient bone marrow in the LDLr−/− model reduces macrophage content in established plaques.	[60]
CXCR3	Blockade in the LDLr−/− model using the antagonist NBI-74330 inhibits atherosclerosis by reducing activated T-cells and increasing Tregs. Deficiency in the ApoE−/− model reduces early atherosclerotic lesion development in the abdominal aorta associated with upregulation of IL-10, IL-18BP, eNOS and Tregs.	[61], [62]
CXCR4	Functional blockade in the ApoE−/− or the LDLr−/− models promotes atherosclerosis through deranged neutrophil homeostasis. Antagonists reduce neointima formation without impairing endotheliazation following carotid wire injury in the ApoE−/− model. Deficiency of endothelial CXCR4 attenuates reendothelialization and stimulates neointima hyperplasia following vascular injury in ApoE−/− mice.	[63], [64], [65], [66]
CXCR6	Deficiency in the ApoE−/− model decreases plaque formation and reduces T-cell and macrophage content.	[67]
CXCR7	Activation in the ApoE−/− model improves hyperlipidemia by stimulating cholesterol uptake in adipose tissue.	[68]
CX3CR1	Deficiency in the ApoE−/− model decreases atherosclerosis associated with reduced recruitment of macrophages and DCs. Antagonist inhibits atherosclerosis in both ApoE−/− and LDLr−/− models by modulating monocyte trafficking.	[69], [70], [71], [72]