CXCR6 promotes atherosclerosis by supporting T-cell homing, interferon-gamma production, and macrophage accumulation in the aortic wall.
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+ 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.


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(-/-)) mice. We found that CXCR6(GFP/GFP)/ApoE(-/-) mice fed a Western diet for 17 weeks or a chow diet for 56 weeks had decreased atherosclerosis compared with ApoE(-/-) controls. Flow cytometry analysis of the aortas from CXCR6(GFP/GFP)/ApoE(-/-) mice showed that the reduction of atherosclerosis was accompanied by a decreased percentage of CXCR6+ T cells within the aortas. Short-term homing experiments demonstrated that CXCR6 is involved in the recruitment of CXCR6+ leukocytes into the atherosclerosis-prone aortic wall. The reduced percentage of CXCR6+ T cells within the aortas resulted in significantly diminished production of interferon-gamma and reduction of CD11b+/CD68+ macrophages in the aorta.


CONCLUSIONS
These data provide evidence for a proatherosclerotic role of CXCR6. Absence of CXCR6 alters the recruitment of CXCR6+ leukocytes and modulates the local immune response within the aortic wall.
Galkina
Elena
E
Department of Biomedical Engineering and Robert M. Berne Cardiovascular Research Center, University of Virginia, Health Sciences Center, Charlottesville, VA 22908, USA. evg7c@virginia.edu
Harry
Brian L
BL
Ludwig
Andreas
A
Liehn
Elisa A
EA
Sanders
John M
JM
Bruce
Anthony
A
Weber
Christian
C
Ley
Klaus
K
D000818:Animals; D001018:Aortic Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D021381:Protein Transport / Q000276:immunology; D054387:Receptors, CXCR / Q000235:genetics* / Q000276:immunology*; D000075744:Receptors, CXCR6; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D001057:Apolipoproteins E; C482906:Cxcr6 protein, mouse; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma