Fractalkine and atherosclerosis: a new role for a curious chemokine

Despite the introduction of potent lipid-lowering drugs, coronary artery disease remains the leading cause of death in the Western world. Although hypercholesterolemia plays an undeniably important role in atherogenesis, there is growing evidence that inflammatory macrophages and lymphocytes that accumulate within the lesion contribute substantially to coronary artery disease. The signals that recruit these cells, however, have remained obscure. Now, Moatti and colleagues (page 1925) provide evidence that fractalkine, a novel member of the chemokine family of chemotactic cytokines, may be one such signal.

Chemokines are soluble, secreted proteins that direct the migration of specific subsets of leukocytes. Which leukocytes respond to which chemokines is determined by the set of chemokine receptors expressed on a particular cell. Fractalkine is a unique chemokine: it exists both as a soluble, chemotactic protein and as a membrane-bound, cell-adhesion molecule on endothelial cells. In both cases, its actions are mediated by CX₃CR1, a 7-transmembrane receptor that is expressed on monocytes, T cells, and NK cells.

Moatti and colleagues show that a polymorphism in CX₃CR1 results in fewer copies of the receptor on the cell surface and a reduced incidence of coronary artery disease in humans, independent of other well-established risk factors. These findings suggest that fractalkine plays an important role in monocyte/T-cell recruitment to the vessel wall. In addition, the findings are consistent with recent studies demonstrating that monocyte chemoattractant protein 1, another member of the chemokine family, is critical for fatty-streak formation in murine models of atherosclerosis. Taken together, these results suggest that impaired recruitment of inflammatory cells does indeed translate into protection from advanced coronary artery disease, and identify chemokines as potentially important new therapeutic targets for the treatment of atherosclerosis. Whether interrupting monocyte/macrophage recruitment late in the course of the disease will be beneficial remains to be determined.