Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability

J Cereb Blood Flow Metab. 2005 May;25(5):593-606. doi: 10.1038/sj.jcbfm.9600055.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Blood-Brain Barrier / drug effects*
  • Blotting, Western
  • Brain / cytology
  • Brain / drug effects*
  • Capillary Permeability / drug effects*
  • Cells, Cultured
  • Chemokine CCL2 / pharmacology*
  • Chemotaxis, Leukocyte / drug effects
  • Coculture Techniques
  • Endothelial Cells / drug effects*
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Receptors, CCR2
  • Receptors, Chemokine / drug effects
  • Receptors, Chemokine / genetics
  • Tight Junctions / drug effects


  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Receptors, CCR2
  • Receptors, Chemokine