title: Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability.
abstract: 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 microL/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 microL/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 approximately 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.
authors.affiliation: Department of Neurosurgery, Pulmonary and Critical Care Medicine, Ann Arbor, MI 48109-0532, USA.
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Stamatovic
authors.forename: Parvin
authors.initials: P
authors.lastname: Shakui
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Anuska V
authors.initials: AV
authors.lastname: Andjelkovic
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics; D019108:Tight Junctions / Q000187:drug effects
chemical_list: C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine