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Atherogenic Lipids Induce High-Density Lipoprotein Uptake and Cholesterol Efflux in Human Macrophages by Up-Regulating Transmembrane Chemokine CXCL16 without Engaging CXCL16-Dependent Cell Adhesion¹

Jana Barlic^*,, Wenjia Zhu^* and Philip M. Murphy^2,*

^* Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104

Atherosclerosis is a complex pathologic process in which chemokine-mediated leukocyte accumulation in arterial walls is thought to be an important mechanism of pathogenesis. An interesting exception to this paradigm is the chemokine CXCL16, also known as the scavenger receptor for phosphatidylserine and oxidized low density lipoprotein, which is highly expressed in mouse and human atherosclerotic lesions, yet appears to be atheroprotective. In this study, we address potential mechanisms responsible for this activity. Consistent with its presence in atherosclerotic plaque, we found that atherogenic lipids up-regulated CXCL16 in primary human monocyte-derived macrophages. However, 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, we found that heterotypic adhesion of these cell types occurred in a CXCL16-independent manner. Instead we found that 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. Thus, our findings support the hypothesis that CXCL16 mediates atheroprotection through its scavenger role in macrophages and not by cell-cell adhesion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part by Wellcome Trust Career Development Award in Basic Biomedical Sciences Reference 081169 (to J.B.).

² Address correspondence and reprint requests to Dr. Philip M. Murphy, Building 10, Room 11N113, 9000 Rockville Pike, National Institutes of Health, Bethesda, MD 20892. E-mail address: pmm{at}nih.gov

³ Abbreviations used in this paper: oxLDL, oxidized low density lipoprotein; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; acLDL, acetyl low density lipoprotein; ApoE, apolipoprotein E; CASMC, coronary artery smooth muscle cell; Dil, 1,1'-dioctadecyl-3,3,3',3'-tetramethylin docarbocyaninet; HDL, high density lipoprotein; 9-HODE, 9-hydroxy-10E,12Z-octadecadienoic acid ester; 13-HODE, 13-hydroxy-9Z,11E-octadecadienoic acid ester; LDL, low density lipoprotein; Mo, monocyte; M, macrophage; PGPC, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine; POV-PC, 1-palmitoyl-2-(5-oxo valeroyl)-sn-glycero-3-phosphocholine; RCT, reverse cholesterol transport; SMC, smooth muscle cell; SR-A, scavenger receptor-A; SR-BI, scavenger receptor-BI; sRNAi, small RNA interference.

⁴ The online version of this article contains supplemental material.

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