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Chemokine and Matrix Metalloproteinases1
* Department of Pathology, University of Wisconsin-Madison, Madison, WI 53706; and
Neuroscience Training Program and
Cellular and Molecular Pathology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792
Dendritic cells (DCs) accumulate in the CNS during inflammatory diseases, but the exact mechanism regulating their traffic into the CNS remains to be defined. We now report that MIP-1
increases the transmigration of bone marrow-derived, GFP-labeled DCs across brain microvessel endothelial cell monolayers. Furthermore, occludin, an important element of endothelial tight junctions, is reorganized when DCs migrate across brain capillary endothelial cell monolayers without causing significant changes in the barrier integrity as measured by transendothelial electrical resistance. We show that DCs produce matrix metalloproteinases (MMP) -2 and -9 and GM6001, an MMP inhibitor, decreases both baseline and MIP-1-induced DC transmigration. These observations suggest that DC transmigration across brain endothelial cell monolayers is partly MMP dependent. The migrated DCs express higher levels of CD40, CD80, and CD86 costimulatory molecules and induce T cell proliferation, indicating that the transmigration of DCs across brain endothelial cell monolayers contributes to the maintenance of DC Ag-presenting function. The MMP dependence of DC migration across brain endothelial cell monolayers raises the possibility that MMP blockers may decrease the initiation of T cell recruitment and neuroinflammation in the CNS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant RO1-NS 37570-01A2 (to Z.F.).
2 Current address: Department of Neurology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115.
3 Address correspondence and reprint requests to Dr. Zsuzsanna Fabry, Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 1300 University Avenue, 6130 MSC, Madison, WI 53706. E-mail address: zfabry{at}wisc.edu
4 Abbreviations used in this paper: DC, dendritic cell; BBB, blood-brain barrier; MS, multiple sclerosis; MMP, matrix metalloproteinase; TEER, transendothelial electrical resistance; BCEC, brain capillary endothelial cell; SEM, scanning electron microscopy; ZO-1, zona occludens-1; Tg, transgenic; NGAL, neutrophil gelatinase B-associated lipocalin; CLSM, confocal laser scanning microscopy.
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