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(American Journal of Pathology. 2006;168:1385-1395.)
© 2006 American Society for Investigative Pathology

Up-Regulated Expression of the CXCR2 Ligand KC/GRO- in Atherosclerotic Lesions Plays a Central Role in Macrophage Accumulation and Lesion Progression

William A. Boisvert^*, David M. Rose, Kristen A. Johnson, Maria E. Fuentes, Sergio A. Lira^¶, Linda K. Curtiss^* and Robert A. Terkeltaub

From the Department of Immunology,^* The Scripps Research Institute, La Jolla, California; Vascular Medicine Research Unit, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, Massachusetts; the Department of Medicine, Veteran’s Administration Medical Center, University of California, San Diego, San Diego, California; Roche Biosciences, Palo Alto, California; and the Immunobiology Center,^¶ Mount Sinai School of Medicine, New York, New York

Macrophage-mediated inflammation is central to atherogenesis. We have determined previously that the CXC chemokine receptor CXCR2 is involved in advanced atherosclerosis. We sought to determine whether one of the ligands of CXCR2, KC/GRO-, can also modulate atherogenesis. KC/GRO-^–/– mice were generated and mated with the atherosclerosis-prone LDLR^–/– mice. There was a significant reduction in atherosclerosis in mice lacking KC/GRO-; however, this reduction was only approximately half that seen previously in mice lacking CXCR2 in the leukocyte. To determine whether CXCR2 is involved in the early formation of atherosclerosis, leukocyte-specific CXCR2^–/– chimeric mice on LDLR^–/– background were generated. Early fatty streak lesion formation in these mice was not affected by leukocyte CXCR2 deficiency whereas lesions were less developed in mice lacking leukocyte CXCR2 when atherosclerosis was allowed to progress to the intermediate stage. Macrophages were relatively sparse in the lesions of leukocyte CXCR2^–/– mice despite robust MCP-1 expression. These studies indicate that KC/GRO-/CXCR2 does not play a critical role in recruitment of macrophages into early atherosclerotic lesions but both arterial KC/GRO- and leukocyte-specific CXCR2 expression are central to macrophage accumulation in established fatty streak lesions.

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