Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans
David H. McDermott, … , Dhavalkumar D. Patel, Philip M. Murphy
David H. McDermott, … , Dhavalkumar D. Patel, Philip M. Murphy
Published April 15, 2003
Citation Information: J Clin Invest. 2003;111(8):1241-1250. https://doi.org/10.1172/JCI16790.
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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.

Authors

David H. McDermott, Alan M. Fong, Qiong Yang, Joan M. Sechler, L. Adrienne Cupples, Maya N. Merrell, Peter W.F. Wilson, Ralph B. D’Agostino, Christopher J. O’Donnell, Dhavalkumar D. Patel, Philip M. Murphy

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Figure 3

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Calcium mobilization by CX3CR1-M280 is defective. Data represent the mea...
Calcium mobilization by CX3CR1-M280 is defective. Data represent the mean ± SEM of one representative experiment (a) and three independent experiments (b). The cell lines used were the same as those analyzed in Figure 1. (a) Kinetics. Shown are real-time fura-2 AM fluorescence traces of untransfected HEK 293 cells or HEK 293 cells expressing the recombinant receptor indicated by the key at upper right in response to 1 μM soluble FKN added at 19 seconds. (b) Concentration dependence. Shown is the maximal fura-2 AM fluorescence change of HEK 293 cells stably transfected with the indicated construct in response to the indicated concentration of FKN. P values at the top of each set of bars compare results for CX3CR1-M280 and CX3CR1-WT by two-tailed Student t test.