CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival

CX(3)CR1 is a chemokine receptor with a single ligand, the membrane-tethered chemokine CX(3)CL1 (fractalkine). All blood monocytes express CX(3)CR1, but its levels differ between the main 2 subsets, with human CD16(+) and murine Gr1(low) monocytes being CX(3)CR1(hi). Here, we report that absence of either CX(3)CR1 or CX(3)CL1 results in a significant reduction of Gr1(low) blood monocyte levels under both steady-state and inflammatory conditions. Introduction of a Bcl2 transgene restored the wild-type phenotype, suggesting that the CX(3)C axis provides an essential survival signal. Supporting this notion, we show that CX(3)CL1 specifically rescues cultured human monocytes from induced cell death. Human CX(3)CR1 gene polymorphisms are risk factors for atherosclerosis and mice deficient for the CX(3)C receptor or ligand are relatively protected from atherosclerosis development. However, the mechanistic role of CX(3)CR1 in atherogenesis remains unclear. Here, we show that enforced survival of monocytes and plaque-resident phagocytes, including foam cells, restored atherogenesis in CX(3)CR1-deficent mice. The fact that CX(3)CL1-CX(3)CR1 interactions confer an essential survival signal, whose absence leads to increased death of monocytes and/or foam cells, might provide a mechanistic explanation for the role of the CX(3)C chemokine family in atherogenesis.