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

CX₃CR1 is a chemokine receptor with a single ligand, the membrane-tethered che- mokine CX₃CL1 (fractalkine). All blood monocytes express CX₃CR1, but its lev- els differ between the main 2 subsets, with human CD16⁺ and murine Gr1^lowmonocytes being CX₃CR1^hi. Here, we re- port that absence of either CX₃CR1 or CX₃CL1 results in a significant reduction of Gr1^low blood monocyte levels under both steady-state and inflammatory con- ditions. Introduction of a Bc12 transgene restored the wild-type phenotype, sug- gesting that the CX₃C axis provides an essential survival signal. Supporting this notion, we show that CX₃CL1 specifically rescues cultured human monocytes from induced cell death. Human CX₃CR1 gene polymorphisms are risk factors for athero- sclerosis and mice deficient for the CX₃C receptor or ligand are relatively protected from atherosclerosis development. How- ever, the mechanistic role of CX₃CR1 in atherogenesis remains unclear. Here, we show that enforced survival of mono- cytes and plaque-resident phagocytes, including foam cells, restored atherogen- esis in CX₃CR1-deficent mice. The fact that CX₃CL1-CX₃CR1 interactions confer an essential survival signal, whose ab- sence leads to increased death of mono- cytes and/or foam cells, might provide a mechanistic explanation for the role of the CX ₃C chemokine family in atherogen- esis.