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Blood, 22 January 2009, Vol. 113, No. 4, pp. 963-972.
Prepublished online as a Blood First Edition Paper on October 29, 2008; DOI 10.1182/blood-2008-07-170787.
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Submitted July 25, 2008
Accepted October 7, 2008
CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival
Limor Landsman, Liat Bar-On, Alma Zernecke, Ki-Wook Kim, Rita Krauthgamer, Erdenechimeg Shagdarsuren, Sergio A Lira, Irving L Weissman, Christian Weber, and Steffen Jung*
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
Institute for Molecular Cardiovascular Research, RWTH University Hospital, Aachen, Germany
Immunobiology Center, Mount Sinai School of Medicine, New York, NY, United States
Pathology Department, Beckman Center, Stanford University School of Medicine, Stanford, CA, United States
* Corresponding author; email: s.jung{at}weizmann.ac.il.
CX3CR1 is a chemokine receptor with a single ligand, the membrane-tethered chemokine CX3CL1 (fractalkine). All blood monocytes express CX3CR1, but its levels differ between the main two subsets, with human CD16+ and murine Gr1low monocytes being CX3CR1hi. Here we report that absence of either CX3CR1 or CX3CL1 results in a significant reduction of Gr1low blood monocyte levels under both steady state and inflammatory conditions. Introduction of a Bcl2 transgene restored the wild type phenotype, suggesting 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 atherosclerosis and mice deficient for the CX3C receptor or ligand are relatively protected from atherosclerosis development. However, the mechanistic role of CX3CR1 in atherogenesis remains unclear. Here we show that enforced survival of monocytes and plaque-resident phagocytes, including foam cells, restored atherogenesis in CX3CR1-deficent mice. The fact that CX3CL1-CX3CR1 interactions confer an essential survival signal, whose absence lead to increased death of monocytes and/or foam cells, might provide a mechanistic explanation for the role of the CX3C chemokine family in atherogenesis.
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