1. ¹Department of Neurosurgery, Pulmonary and Critical Care Medicine, Ann Arbor, Michigan, USA
2. ²Department of Molecular and Integrative Physiology, Pulmonary and Critical Care Medicine, Ann Arbor, Michigan, USA
3. ³Department of Internal Medicine, Pulmonary and Critical Care Medicine, Ann Arbor, Michigan, USA
4. ⁴Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
5. ⁵Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands

Correspondence: Dr AV Andjelkovic, Departments of Neurosurgery and Pathology, University of Michigan, R5550 Kresge I, Ann Arbor, MI 48109-0532, USA. E-mail: anuskaa@umich.edu

Received 27 September 2004; Revised 12 November 2004; Accepted 5 December 2004; Published online 2 February 2005.

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 (0.0960.008 versus 0.0310.005 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 0.0960.006 and 0.0320.007 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 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.