Dendritic cell transmigration through brain microvessel endothelium is regulated by MIP-1alpha chemokine and matrix metalloproteinases.
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-1alpha 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-1alpha-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.
Zozulya
Alla L
AL
Department of Pathology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Reinke
Emily
E
Baiu
Dana C
DC
Karman
Jozsef
J
Sandor
Matyas
M
Fabry
Zsuzsanna
Z
D000818:Animals; D001921:Brain / Q000098:blood supply*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000494:pharmacology / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D008213:Lymphocyte Activation; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D062793:Occludin; D019108:Tight Junctions / Q000737:chemistry / Q000648:ultrastructure
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D004791:Enzyme Inhibitors; D019402:Macrophage Inflammatory Proteins; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D049452:Green Fluorescent Proteins; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9