Targeted Disruption of the Scavenger Receptor and Chemokine CXCL16 Accelerates Atherosclerosis

Abstract

Background— The uptake of oxidized low-density lipoprotein (OxLDL) by macrophage scavenger receptors is thought to be a key process in the formation of foam cells, the hallmark of early atherosclerotic lesions. CXCL16/scavenger receptor for phosphatidylserine and OxLDL is a multifunctional chemokine that exhibits scavenger receptor activity toward oxidized lipids in a membrane-bound configuration and may be shed to serve as a chemoattractant for T helper 1–polarized T lymphocytes. These properties, as well as the expression of CXCL16 in human and mouse atheroma, suggest that CXCL16 plays a role in atherosclerosis. Methods and Results— To examine the role of CXCL16 in plaque formation, we created CXCL16-deficient mice ( CXCL16 −/− ) and bred them with mice deficient in the LDL receptor ( LDLR −/− ). In vitro, macrophages from CXCL16 −/− mice have a significant reduction in the capacity to bind and internalize OxLDL. We found that CXCL16 −/− / LDLR −/− mice have accelerated atherosclerosis, enhanced macrophage recruitment to the aortic arch, and more abundant mRNA for monocyte chemotactic protein-1 and tumor necrosis factor-α. Conclusions— These data suggest that scavenger receptor activity mediated by CXCL16 in vivo is atheroprotective, and they contrast with studies that document protection from atherosclerosis in scavenger receptor class A- and CD36-deficient mice.