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The Journal of Neuroscience, December 1, 2001, 21(23):9214-9223
The Chemokine Receptor CCR2 Mediates the Binding and
Internalization of Monocyte Chemoattractant Protein-1 along Brain
Microvessels
Kirk A.
Dzenko1,
Anuska
V.
Andjelkovic1,
William A.
Kuziel2, and
Joel S.
Pachter1
1 Blood-Brain Barrier Laboratory, Department of
Pharmacology, University of Connecticut Health Center, Farmington,
Connecticut 06030, and 2 Department of Molecular Genetics
and Microbiology and Institute for Cellular and Molecular Biology,
University of Texas, Austin, Texas 78712
Previous results from this laboratory revealed the presence of
high-affinity saturable binding sites for monocyte chemoattractant protein-1 (MCP-1) along human brain microvessels (Andjelkovic et al.,
1999; Andjelkovic and Pachter, 2000), which suggested that CC chemokine
receptor 2 (CCR2), the recognized receptor for this chemokine, was
expressed by the brain microvascular endothelium. To test the role of
CCR2 directly in mediating MCP-1 interactions with the brain
microvasculature, we assessed MCP-1 binding activity in murine
brain microvessels isolated from wild-type mice and from CCR2 ( /)
mice engineered to lack this receptor. Results demonstrate that MCP-1
binding is greatly attenuated in microvessels prepared from CCR2
(/) mice compared with wild-type controls. Moreover, microvessels
from wild-type mice exhibited MCP-1-induced downmodulation in MCP-1
binding and a recovery of binding activity that was not dependent on
de novo protein synthesis. Furthermore, MCP-1 was
shown to be internalized within wild-type microvessels, but not within
microvessels obtained from CCR2 (/) mice, additionally demonstrating that CCR2 is obligatory for MCP-1 endocytosis. Last, internalization of MCP-1, but not transferrin, was observed to be
inhibited by disruption of caveolae. Internalized MCP-1 also colocalized at some sites with caveolin-1, a major protein of caveolae,
implying that this chemokine is endocytosed, in part, via
nonclathrin-coated vesicles. These results prompt consideration that
MCP-1 signals may be relayed across the blood-brain barrier by highly
specialized interactions of this chemokine with its cognate receptor,
CCR2, along brain microvascular endothelial cells.
Key words:
MCP-1; receptors; brain; microvessels; blood-brain
barrier; endothelial cells
Copyright © 2001 Society for Neuroscience 0270-6474/01/21239214-10$05.00/0
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