Brain Advance Access first published online on October 17, 2005
This version published online on October 24, 2005
Brain, doi:10.1093/brain/awh655
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1 Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Department of Neurology, Newcastle General Hospital, Newcastle upon Tyne, UK
* To whom correspondence should be addressed. Chemokines and chemokine receptors play a key role in the transmigration of leucocytes across the blood-brain barrier (BBB). CCR2 is the major receptor for CCL2, a potent monocyte and T cell chemoattractant. CCR2 and CCL2 have been consistently associated with a pathogenic role in experimental autoimmune encephalomyelitis, using knockout and transgenic mice, neutralizing antibodies, peptide antagonists and DNA vaccination. However, the significance of CCL2 and CCR2 in multiple sclerosis is enigmatic, because CCL2 levels are consistently decreased in the CSF of patients with this disease and other chronic neuroinflammatory conditions, despite abundant expression within lesional multiple sclerosis tissues. This study used an in vitro BBB model to test the hypothesis that CCL2 is removed from the extracellular fluid by CCR2-positive migrating cells as they cross the BBB, resulting in decreased CSF CCL2 levels. We showed that CCR2-positive T cells and monocytes migrated selectively across the in vitro BBB, and that CCL2 on the abluminal (tissue) side was consumed by migrating T cells and monocytes. Next, we used a new anti-CCR2 antibody to show that CCR2-positive mononuclear inflammatory cells could be readily detected in appropriate positive control tissues, but that CCR2+ cells were very infrequently found in multiple sclerosis lesions. We then showed that CCR2 receptor density on T cells and monocytes was specifically downregulated upon in vitro BBB transmigration in response to CCL2, but not irrelevant chemokines. These findings document a novel strategy for analysing chemokine receptor function in inflammatory CNS disease, and support the hypothesis that CCL2 is consumed by migrating inflammatory cells, which downregulate CCR2, as they cross the BBB.
Received July 26, 2005
Revised September 7, 2005
Accepted September 12, 2005
Article
Modulating CCR2 and CCL2 at the blood-brain barrier: relevance for multiple sclerosis pathogenesis
2 Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
3 Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA
4 Millenium Pharmaceuticals, Inc, Cambridge, MA, USA; Present address: Abbott Bioresearch Center, Worcester, MA, USA
5 The Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, USA
6 Department of Internal Medicine, Nephrology Section, University of Regensburg, Regensburg, Germany
7 Netherlands Brain Bank, Amsterdam, The Netherlands
8 Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD
9 Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; The Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, USA
Richard M. Ransohoff, E-mail: ransohr{at}ccf.org
Abstract
*These authors contributed equally to this work
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