Targeted disruption of the scavenger receptor and chemokine CXCL16 accelerates atherosclerosis.
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.


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-alpha.


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.
Aslanian
Ara M
AM
Gladstone Institute of Cardiovascular Disease, 1650 Owens St, San Francisco, Calif 94158, USA.
Charo
Israel F
IF
D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000235:genetics* / Q000502:physiology*; D003324:Coronary Artery Disease / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000502:physiology; D011973:Receptors, LDL / Q000378:metabolism; D051116:Receptors, Scavenger / Q000235:genetics* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018932:Chemokine CCL2; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; C498926:Cxcl16 protein, mouse; C482906:Cxcr6 protein, mouse; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein