Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans

Abstract

The chemokine receptor CX3CR1 is a proinflammatory leukocyte receptor specific for the chemokine fractalkine (FKN or CX3CL1). In two retrospective studies, CX3CR1 has been implicated in the pathogenesis of atherosclerotic cardiovascular disease (CVD) based on statistical association of a common receptor variant named CX3CR1-M280 with lower prevalence of atherosclerosis, coronary endothelial dysfunction, and acute coronary syndromes. However, the general significance of CX3CR1-M280 and its putative mechanism of action have not previously been defined. Here we show that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280. This was associated with marked reduction in the kinetics of FKN binding as well as reduced FKN-induced chemotaxis of primary leukocytes from donors homozygous for CX3CR1-M280. We also show that CX3CR1-M280 is independently associated with a lower risk of CVD (adjusted odds ratio, 0.60, P = 0.008) in the Offspring Cohort of the Framingham Heart Study, a long-term prospective study of the risks and natural history of this disease. These data provide mechanism-based and consistent epidemiologic evidence that CX3CR1 may be involved in the pathogenesis of CVD in humans, possibly by supporting leukocyte entry into the coronary artery wall. Moreover, they suggest that CX3CR1-M280 is a genetic risk factor for CVD

CX 3 CR1 Deficiency Confers Protection From Intimal Hyperplasia After Arterial Injury

“…8,9 In addition, the M280 allele is associated with a reduced risk of internal carotid artery (ICA) occlusive disease. 10 Our laboratory has shown that the protein encoded by the M280 allele has impaired adhesive capacity, 7 suggesting that cell adhesion is an important mechanism by which CX 3 CR1 exerts its effect on recruiting cells during vascular inflammation.…”

“…4,5 CX 3 CL1-deficient mice have a reduction in atherosclerotic plaque burden in the innominate artery. 6 In humans, the V249I/T280M variant of CX 3 CR1 is associated with protection from coronary artery disease [7][8][9] and internal carotid artery occlusive disease. 10 While CX 3 CR1 and CX 3 CL1 are emerging as important mediators of vascular disease, the specific mechanisms regulating their involvement remain unclear.…”

Smooth Muscle Cells in Human Atherosclerotic Plaques Express the Fractalkine Receptor CX 3 CR1 and Undergo Chemotaxis to the CX 3 C Chemokine Fractalkine (CX 3 CL1)

“…28,29,35 PBMCs prepared from human donors with different CX3CR1 genotypes exhibit differences in the number of fractalkine-binding sites per cell, and cells transfected with variant receptor show impaired liganddependent cell adhesion. 35 However, the biological rationale for an association between genetic variation in CX 3 CR1 and coronary artery disease has remained unclear. Our study now provides novel data on CX 3 CR1 expression in human coronary atherosclerosis.…”

Genetic factors of age-related macular degeneration

“…CX3CR1, a CX3C chemokine receptor of fraktaline, is known to be polymorphic with two non-synonymous SNPs in the open reading frame, V249I and T280M. Both of these variations ultimately result in reduced chemoattraction by lowering the binding affinity of the receptor to fractalkine and diminishing the number of available binding sites (McDermott et al, 2003).…”