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© The Rockefeller University Press, 0021-9525/1999//403 $5.00
The Journal of Cell Biology, Volume 145, Number 2, , 1999 403-412

Regular Articles

Visualization of Chemokine Binding Sites on Human Brain Microvessels



Anuska V. Andjelkovic*, Dennis D. Spencer{ddagger}, and Joel S. Pachter*

* Blood-Brain Barrier Laboratory, Department of Pharmacology, University of Connecticut Health Center, Farmington, Connecticut 06030; and {ddagger} Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510

The chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1{alpha} (MIP-1{alpha}) aid in directing leukocytes to specific locales within the brain and spinal cord during central nervous system inflammation. However, it remains unclear how these chemokines exert their actions across a vascular barrier, raising speculation that interaction with endothelial cells might be required. Therefore, experiments were performed to determine whether binding domains for these chemokines exist along the outer surface of brain microvessels, a feature that could potentially relay chemokine signals from brain to blood. Using a biotinylated chemokine binding assay with confocal microscopy and three-dimensional image reconstruction, spatially resolved binding sites for MCP-1 and MIP-{alpha} around human brain microvessels were revealed for the first time. Binding of labeled MCP-1 and MIP-1{alpha} could be inhibited by unlabeled homologous but not heterologous chemokine, and was independent of the presence of heparan sulfate, laminin, or collagen in the subendothelial matrix. This is the first evidence of specific and separate binding domains for MCP-1 and MIP-1{alpha} on the parenchymal surface of microvessels, and highlights the prospect that specific interactions of chemokines with microvascular elements influence the extent and course of central nervous system inflammation.

Key Words: chemokine • monocyte chemoattractant protein • macrophage inflammatory protein-1{alpha} • binding • microvessels

Abbreviations used in this paper: CNS, central nervous system; DARC, Duffy antigen receptor for chemokines; GAG, glycosaminoglycan; MCP-1, monocyte chemoattractant protein-1; MIP-1{alpha}, macrophage inflammatory protein-1{alpha}; PBM, peripheral blood monocytes; rh, recombinant human.

The authors wish to sincerely express their deep appreciation to Drs. Carol Petito and H. Ronald Zielke, Co-directors of the Brain and Tissue Banks For Developmental Disorders, at the University of Miami and the University of Maryland, respectively, as well as to the support staff at all institutions that provided tissue samples. A further debt of gratitude is offered to Mr. Frank Morgan and Ms. Susan Krueger, of the University of Connecticut Center for Biomedical Imaging Technology, for their invaluable assistance in generating three-dimensional images and quantifying chemokine binding, and to Drs. John Shanley and Diane Biegel for helpful discussions.


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