9.B.173 The Chemokine, CXCL16 (CXCL16) Family
In atherosclerosis, chemokine-mediated leukocyte accumulation in arterial walls is thought to provide an important mechanism of pathogenesis. However, the chemokine, CXCL16, also known as the scavenger receptor for phosphatidylserine and oxidized low density lipoprotein, is highly expressed in mouse and human atherosclerotic lesions, yet appears to be atheroprotective. Barlic et al. 2009 showed that atherogenic lipids up-regulated CXCL16 in primary human monocyte-derived macrophages while the same lipids down-regulated the CXCL16-targeted protease ADAM10, resulting in preferential expression of CXCL16 as the transmembrane form, not the shed form. Although transmembrane CXCL16 is known to mediate cell-cell adhesion by binding its receptor CXCR6, and atherogenic lipids are known to stimulate macrophage adhesion to coronary artery smooth muscle cells, heterotypic adhesion of these cell types occurred in a CXCL16-independent manner. In macrophages, CXCL16 promoted internalization of both oxidized low density lipoprotein and high density lipoprotein, as well as release of cholesterol. Moreover, CXCL16 deficiency in macrophages interfered with oxidized low density lipoprotein-induced up-regulation of atheroprotective genes: adenosine triphosphate-binding cassette transporter A1 and G1 as well as apolipoprotein E. These findings support the hypothesis that CXCL16 mediates atheroprotection through its scavenger role in macrophages and not by cell-cell adhesion (Barlic et al. 2009).