Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice.
BACKGROUND
Fractalkine (CX3CL1), a CX3C chemokine, is expressed in the vessel wall and mediates the firm adhesion and chemotaxis of leukocytes expressing its receptor, CX3CR1. A polymorphism in the CX3CR1 gene is associated with low CX3CR1 expression and reduced risk of acute coronary disease in humans.


RESULTS
We generated CX3CR1-deficient mice (CX3CR1(-/-)) by targeted gene disruption and crossed them with the proatherogenic apolipoprotein E-deficient mice (apoE(-/-)). Here we show that the extent of lipid-stained lesions in the thoracic aorta was reduced by 59% in CX3CR1/apoE double knockout mice compared with their CX3CR1(+/+)/apoE(-/-) littermates. The development of atherosclerosis in the aortic sinus was also markedly altered in the double knockout mice, with 50% reduction in macrophage accumulation. Although lesions of CX3CR1(-/-) mice were smaller in size, they retained a substantial accumulation of smooth muscle cells and collagen, features consistent with a stable plaque phenotype. Finally, CX3CR1(+/-)/apoE(-/-) mice showed the same reduction in atherosclerosis as the CX3CR1(-/-)/apoE(-/-) mice.


CONCLUSIONS
The CX3CR1-CX3CL1 pathway seems to play a direct and critical role in monocyte recruitment and atherosclerotic lesion development in a mouse model of human atherosclerosis.
Combadière
Christophe
C
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md 20892, USA.
Potteaux
Stéphane
S
Gao
Ji-Liang
JL
Esposito
Bruno
B
Casanova
Saveria
S
Lee
Eric J
EJ
Debré
Patrice
P
Tedgui
Alain
A
Murphy
Philip M
PM
Mallat
Ziad
Z
D000483:Alleles; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D018390:Gene Targeting; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D019707:Receptors, Chemokine / Q000235:genetics* / Q000502:physiology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000502:physiology*; D015728:Receptors, HIV / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D008565:Membrane Proteins; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015728:Receptors, HIV