Decreased Atherosclerotic Lesion Formation in CX3CR1/Apolipoprotein E Double Knockout Mice

Abstract

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. Methods and Results-We generated CX3CR1-deficient mice (CX3CR1 Ϫ/Ϫ ) by targeted gene disruption and crossed them with the proatherogenic apolipoprotein E-deficient mice (apoE Ϫ/Ϫ ). 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 ϩ/ϩ / apoE Ϫ/Ϫ 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 Ϫ/Ϫ 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 ϩ/Ϫ /apoE Ϫ/Ϫ mice showed the same reduction in atherosclerosis as the CX3CR1 Ϫ/Ϫ / apoE Ϫ/Ϫ 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.

Chemokine Receptor CX3CR1 Mediates Skin Wound Healing by Promoting Macrophage and Fibroblast Accumulation and Function

“…Fifth, labeled BM-derived cells from WT donor mice accumulated in large numbers in wound sites of both recipient WT and CX3CR1 KO mice on day 6 after injury, a time point when macrophages are the major leukocyte subset found in the wound, whereas accumulation was markedly reduced when the donor mouse was CX3CR1 KO. A similar role for CX3CR1 in mediating macrophage accumulation in diseased tissue has been reported in a mouse model of atherosclerosis, and CX3CR1 has been implicated directly in human atherosclerotic cardiovascular disease (26,45,46). However, heretofore the chemokine signals regulating macrophage accumulation in healing wounds had not been clearly delineated.…”

“…Male CX3CR1 knockout (KO) mice, generated as previously described (26), were backcrossed onto C57BL/6 mice from Taconic Farms for 10 generations. Control C57BL/6 mice were obtained from Taconic Farms.…”

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…For example, defective apoptotic cell clearance is thought to be involved in atherogenesis, 58 and intriguingly FKN deficiency has been associated with this disease. 59,60 However, to what extent FKN released during apoptosis is involved in this pathogenesis has not been determined. The deficiency of CX3CR1 has also been associated with decreased numbers of macrophages in B-cell germinal centers.…”

Chemokines in tumor angiogenesis and metastasis

“…Recent studies have suggested that the interaction of FKN and CX 3 CR1 contributes to the pathogenesis of atherosclerosis [120,121] and kidney diseases through the firm adhesion of leukocytes to endothelial cells [30,122]. FKN has been also shown to participate in the pathogenesis of rheumatoid arthritis, probably by increasing the angiogenic process through endothelial cell activation [117][118][119].…”