Abstract
Fractalkine (CX3CL1, FKN) is expressed in the inflamed vascular wall and absence of FKN reduces atherogenesis. Whether FKN is expressed throughout all stages of atherosclerotic disease and whether it directly contributes to monocyte recruitment to atherosclerotic lesions is not known. We collected human atherosclerotic plaque material and blood samples from patients with carotid artery disease undergoing endarterectomy. Plaques were analyzed by immunohistochemistry and qPCR. We found that FKN is expressed at all stages of atherosclerotic lesion formation, and that the number of FKN-expressing cells positively correlates with the number of CX3CR1-positive cells in human carotid artery plaques. In the circulation, soluble FKN levels are significantly elevated in the presence of high-grade (sub-occlusive) stenosis. To determine the role of the FKN-CX3CR1 axis for monocyte adhesion in vivo we then performed intravital videofluorescence microscopy of the carotid artery in ApoE−/− mice. Notably, FKN-CX3CR1 interactions are critical for recruitment of circulating monocytes to the injured atherosclerotic vascular wall. Thus, this chemokine dyad could represent an attractive target for anti-atherosclerotic strategies.
Highlights
Rupture of carotid artery atherosclerotic plaque causes transient ischemic attack and stroke
FKN positive staining was found in various areas of the vascular wall (Figure 1) and comprised macrophages, smooth muscle cells and endothelium, including intraplaque microvessels (Figure 1, 2, S3, S4)
We determined a positive correlation between the number of FKNpositive and CX3CR1-positive events, which was more significant in advanced lesions (Figure 3B)
Summary
Rupture of carotid artery atherosclerotic plaque causes transient ischemic attack and stroke. In mouse models of atherosclerosis, absence of FKN or its receptor CX3CR1 protects from atherosclerotic lesion formation [7,8,9] and humans with a polymorphism for CX3CR1 exhibit a decreased risk for developing coronary artery disease [10,11,12]. It is unknown if FKN is expressed in early stages of lesion development and whether FKN directly modulates leukocyte recruitment from circulating blood in vivo. It needs to be determined whether circulating monocytes can bind directly to plaque and if CX3CR1 was involved in this process
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