Abstract 1739: Fractalkine/CX3CR1 and MCP-1/CCR2 Act in a Complementary Way to Promote the Development of Atherosclerosis
Both Fractalkine/CX3CR1 and MCP-1/CCR2 pathways are known to be essential in leukocyte recruitment, which is the first step in the development of atherosclerosis. In vitro studies suggest that fractalkine/CX3CR1 and MCP-1/CCR2 proceed in a different manner to promote leukocyte migration into the vessel wall. Unlike MCP-1, Fractalkine is able to mediate leukocyte firm adhesion independently of integrin activation. Moreover, Fractalkine preferentially mediates arrest and migration of CD16+ monocytes while MCP-1 triggers transendothelial migration of CD16− monocytes. Thus, we hypothesized that Fractalkine/CX3CR1 and MCP-1/CCR2 may operate in a complementary way to promote leukocyte migration into atherosclerotic lesions. To that end, we analyzed the effect of simultaneous deficiency in CX3CR1 and in MCP-1 in atherosclerosis by generating triple knockout mice CX3CR1−/−/MCP-1−/−/apoE−/− and compared them to simple or double knockout mice. After 25 weeks on chow diet, we found a very marked 85% decrease in lesion size in CX3CR1−/−/MCP-1−/−/apoE−/− compared to apoE−/−mice (55 661 ± 30 342μm2, versus 353 707 ± 18 984 μm2; P<0.001), despite similar cholesterol levels. This inhibition of plaque development was significantly more pronounced (P<0.02) than the 43% or 55% reduction in lesion size obtained in CX3CR1−/−/apoE−/− (208 625 ± 50 613 μm2) or MCP-1−/−/apoE−/− mice (160 059 ± 18 449μm2), suggesting complementary roles of CX3CR1 and MCP-1 in atherosclerosis. Similar results were obtained in a model of chimeric LDLr−/− mice transplanted with bone marrow isolated from each of the simple knockouts, from the double knockout or from the wild type mice. Using an organ culture model, we found that CX3CR1 and MCP-1 contribute additive roles regarding monocyte adhesion on carotid endothelium. CX3CR1−/− or MCP-1−/−mononuclear cells showed 18% and 47% reduction in adhesion capacity, respectively, whereas cells deficient in both MCP-1 and CX3CR1 showed 70% reduction in adhesion capacity. In conclusion, we show for the first time that 2 different chemokine/chemokine receptor pathways, Fractalkine/CX3CR1 and MCP-1/CCR2, act synergistically to promote leukocyte recruitment and atherosclerosis development.