CXCR6 Promotes Atherosclerosis by Supporting T-Cell Homing, Interferon-γ Production, and Macrophage Accumulation in the Aortic Wall

Abstract

Background-T lymphocytes are thought to be important in atherosclerosis, but very little is known about the mechanisms of lymphocyte recruitment into atherosclerosis-prone aortas. In this study we tested the hypothesis that CXCR6, a chemokine receptor that is expressed on a subset of CD4 ϩ T helper 1 cells and natural killer T cells, is involved in lymphocyte homing into the aortic wall and modulates the development and progression of atherosclerosis. Methods and Results-To investigate the role of CXCR6 in the development and progression of atherosclerosis, we bred CXCR6-deficient (CXCR6 GFP/GFP ) mice with apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice. We found that CXCR6 Key Words: atherosclerosis Ⅲ immune system Ⅲ leukocytes Ⅲ lymphocytes Ⅲ vessels A therosclerotic lesions are characterized by lipid accumulation, cell death, fibrosis, and chronic vascular inflammation. 1 The body of evidence is growing that T and B lymphocytes, dendritic cells, and macrophages reside within the noninflamed aortic wall, and a significant influx of macrophages and T cells correlates with the development and progression of atherosclerosis. [2][3][4] The molecular mechanisms, kinetics of trafficking, and retention of different types of immune cells within the noninflamed and atherosclerosisprone aortic wall are not well defined. Most of the focus to date has been on the ability of monocytes to migrate to the atherosclerotic wall. 5 P-selectin, vascular cell adhesion molecule-1 (VCAM-1), P-selectin glycoprotein ligand-1 (PSGL-1), and ␣ 4 ␤ 1 integrin (VLA-4) are all involved in monocyte recruitment into atherosclerotic plaques, 6 and the chemokines CCL5 (regulated on activation, normal T cell expressed and secreted [RANTES]) and CXCL1 (keratinocyte-derived chemokine [KC]) are responsible for triggering monocyte adhesion on the atherosclerotic endothelium. [7][8][9] Lymphocyte trafficking into normal and atherosclerotic aortas is partially L-selectin dependent, 2 but little is known about other potential molecular mechanisms of lymphocyte recruitment. Clinical Perspective p 1811CXCR6 is a chemokine receptor expressed on some T helper 1 (Th1) and natural killer T (NKT) cells found in rheumatoid joints and inflamed livers. 10 CXCR6, also known as Bonzo/STRL33/TYMSTR, 11 is expressed on subpopulations of CD4 ϩ effector memory T cells, 10 on V␣ 24 ϩ NKT cells, 12,13 a Forkhead Box P3 The disintegrin and metalloproteinase ADAM10 is involved in CXCL16 cleavage from the cell membrane, 21 leading to the release of a soluble protein that functions as a chemoattractant for responsive leukocytes.In addition to its properties as a chemokine, CXCL16 acts also as a scavenger receptor for apoptotic cells, phosphatidylserine, and oxidized low-density lipoprotein. 16,19 Expression of CXCL16 has been reported in atherosclerosis-prone vessels from apolipoprotein-E-deficient (ApoE Ϫ/Ϫ ) mice 23 and human atherosclerotic plaques. 24 Absence of CXCL16 has been shown to accelerate atherosclerosis, enhance macrophage recruitment, and elevate mRNA levels for...

Chemokine CXCL16 Regulates Neutrophil and Macrophage Infiltration into Injured Muscle, Promoting Muscle Regeneration

“…17 We found that CXCL16 is expressed both in regenerating muscle and in infiltrating, Mac-2 positive macrophages ( Figure 1). It is known that the receptor for CXCL16, CXCR6, is present in inflammatory cells, 36,37 and we found its expression is increased in regenerating muscle. These results are compatible with our hypothesis that CXCL16 influences the infiltration of inflammatory cells into injured muscle (Figure 1).…”

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

“…Recent data from studies using mice deficient in either CXCR6 or CXCL16 support a role for both ligand and receptor in atherogenesis [25,26]. Antagonism of the CXCR6:CXCL16 interaction may therefore be of therapeutic potential and a greater understanding of the molecular basis underlying this interaction is highly desirable.…”

CXCL16 Haplotypes in Patients with Human Carotid Atherosclerosis: Preliminary Results

“…Recently, several studies have suggested the proatherogenic role of CXCL16, and it has been shown that the expression of CXCL16 is enriched in the atherosclerotic plaques of humans and murine experimental models of atherosclerosis 11,12) . The absence of the CXCR6 gene attenuates atherosclerosis and decreases the percentage of CXCR6 T-cells within the aortic wall, thus indicating the proatherogenic role of the CXCL16-CXCR6 axis 13) . Despite this evidence, a recent rodent study suggested the atheroprotective effect of CXCL16 14) , and the plasma sol-CXCL16 levels have been reported to be decreased in patients with coronary atherosclerosis 15) .…”