Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 25, Issue 5, Pages 593-606Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/sj.jcbfm.9600055
Keywords
blood-brain barrier; chemokines; MCP-1; inflammation; permeability
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Funding
- NINDS NIH HHS [NS 044907] Funding Source: Medline
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The present study was designed to elucidate the effects of the chemokine monocyte chemoattractant protein (MCP-1) on blood-brain barrier (BBB) permeability. Experiments were conducted under in vitro conditions (coculture of brain endothelial cells and astrocytes) to study the cellular effects of MCP-1 and under in vivo conditions (intracerebral and intracerebroventricular administration of MCP-1) to study the potential contribution of MCP-1 to BBB disruption in vivo. Our results showed that MCP-1 induces a significant increase in the BBB permeability surface area product for fluorescein isothiocyanate (FITC)-albumin under in vivo conditions, particularly during prolonged (3 or 7 days) exposure (0.096 +/- 0.008 versus 0.031 +/- 0.005 mu L/g min in controls at 3 days, P < 0.001). Monocyte chemoattractant protein-1 also enhanced (17-fold compared with control) the permeability of the in vitro BBB (coculture) model. At the cellular level, MCP-1 causes alteration of tight junction (TJ) proteins in endothelial cells (redistribution of TJ proteins determined by Western blotting and loss of immunostaining for occludin, claudin-5, ZO-1, ZO-2). Monocyte chemoattractant protein-1-induced alterations in BBB permeability are mostly realized through the CCR2 receptor. Absence of CCR2 diminishes any effect of MCP-1 on BBB permeability in vitro and in vivo. The permeability surface area product for FITC-albumin after 3 days exposure to MCP-1 was 0.096 +/- 0.006 and 0.032 +/- 0.007 mu L/g min, in CCR2 +/+ and CCR2-/- mice, respectively (P < 0.001). Monocytes/macrophages also participate in MCP-1-induced alterations in BBB permeability in vivo. Monocytes/macrophages depletion (by clodronate liposomes) reduced the effect of MCP-1 on BBB permeability in vivo similar to 2 fold. Our results suggest that, besides its main function of recruiting leukocytes at sites of inflammation, MCP-1 also plays a role in 'opening' the BBB.
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