Published Online
on July 31, 2006

A more recent version of this article appeared on August 8, 2006

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Submitted on February 15, 2006
Revised on May 5, 2006
Accepted on May 30, 2006

Targeted Disruption of the Scavenger Receptor and Chemokine CXCL16 Accelerates Atherosclerosis

Ara M. Aslanian PhD and Israel F. Charo MD, PhD^*

From the Gladstone Institute of Cardiovascular Disease (A.M.A., I.F.C.), San Francisco, Calif, and Cardiovascular Research Institute (I.F.C.), Department of Medicine, University of California, San Francisco, Calif.

^* To whom correspondence should be addressed. E-mail: icharo{at}gladstone.ucsf.edu.

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-.

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.

Key words: atherosclerosis • leukocytes • lipids • chemokines

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