Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/- mice: evidence for independent chemokine functions in atherogenesis.
BACKGROUND
Monocyte-derived foam cells are the hallmark of early atherosclerosis, and recent evidence indicates that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Genetic deletions of monocyte chemoattractant protein-1 (MCP-1, CCL2), fractalkine (CX3CL1), or their cognate receptors, CCR2 and CX3CR1, markedly reduce atherosclerotic lesion size in murine models of atherosclerosis. The aim of this study was to determine whether these 2 chemokines act independently or redundantly in promoting atherogenesis.


RESULTS
We crossed CX3CL1(-/-)ApoE(-/-) and CCR2(-/-)ApoE(-/-) mice to create CX3CL1(-/-)CCR2(-/-)ApoE(-/-) triple knockouts and performed a 4-arm atherosclerosis study. Here, we report that deletion of CX3CL1 in CCR2(-/-) mice dramatically reduced macrophage accumulation in the artery wall and the subsequent development of atherosclerosis. Deletion of CX3CL1 did not reduce the number of circulating monocytes in either "wild-type" ApoE(-/-) mice or CCR2(-/-)ApoE(-/-) mice, which suggests a role for CX3CL1 in the direct recruitment and/or capture of CCR2-deficient monocytes.


CONCLUSIONS
These data provide the first in vivo evidence for independent roles for CCR2 and CX3CL1 in macrophage accumulation and atherosclerotic lesion formation and suggest that successful therapeutic strategies may need to target multiple chemokines or chemokine receptors.
Saederup
Noah
N
Gladstone Institute of Cardiovascular Disease, 1650 Owens St, San Francisco, CA 94158, USA.
Chan
Liana
L
Lira
Sergio A
SA
Charo
Israel F
IF
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000502:physiology; D054428:Chemokine CX3CL1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018925:Chemokines / Q000502:physiology; D005260:Female; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
C515335:Ccr2 protein, mouse; D054428:Chemokine CX3CL1; D018925:Chemokines; D054390:Receptors, CCR2