Blood, 1 April 2001, Vol. 97, No. 7, pp. 1905-1905
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.
Israel F. Charo
University of California
