Dendritic Cell Transmigration through Brain Microvessel Endothelium Is Regulated by MIP-1α Chemokine and Matrix Metalloproteinases

Abstract

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-1α 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-1α-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.

T cell independent mechanism for copolymer‐1‐induced neuroprotection

“…These Cop-1-breakdown products may themselves be neuroprotective, and may be capable of crossing the BBB to mediate their neuroprotective effects. Moreover, these DC can amplify a T cellmediated immune response in the CNS [59], which can further potentiate neuroprotective effects of Cop-1.…”

“…These Cop-1-breakdown products may themselves be neuroprotective, and may be capable of crossing the BBB to mediate their neuroprotective effects. Moreover, these DC can amplify a T cellmediated immune response in the CNS [59], which can further potentiate neuroprotective effects of Cop-1.These data, taken together, provide a novel mechanism of Cop-1 mediated neuroprotection, enhancing its utility for treatment of neurodegenerative and neuroinflammatory disorders. …”

Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection

“…(Christian et al, 1996), we have found no evidence for the presence of plasmacytoid dendritic cells during the first 14 days after VSV infection (Palian et al, unpublished). Indeed, pDCs are reportedly absent from the brain parenchyma, but have been found in brain during chronic inflammation (Ambrosini et al, 2005;Bailey et al, 2007;Matyszak and Perry, 1997;Newman et al, 2005;Rosicarelli et al, 2005;Serafini et al, 2006;Zozulya et al, 2007). IFN-producing cells do not enter the CNS at early times after infection by wt VSV, and peripheral IFN does not cross the blood-brain barrier efficiently (Dafny and Yang, 2005).…”

S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

“…6A) supports this notion. Also, it is tempting to speculate that at proinflammatory doses S100B, by inducing CCL3 expression in microglia, not only might participate in stimulation of microglia migration to the site of damage; it might increase the transmigration of blood-borne inflammatory cells across brain capillaries (77).…”