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Tissue-Type Plasminogen Activator Is a Regulator of Monocyte Diapedesis through the Brain Endothelial Barrier¹

Arie Reijerkerk^2,*, Gijs Kooij^*, Susanne M. A. van der Pol^*, Thomas Leyen^*, Bert van het Hof^*, Pierre-Olivier Couraud, Denis Vivien, Christine D. Dijkstra^* and Helga E. de Vries^*

^* Neuroimmunology Research Group, Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands; Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Institut National de la Santé et de la Recherche Médicale, Paris, France; and University of Caen, Serine Proteases and Pathophysiology of the Neurovascular Unit (SP2U), Institut National de la Santé et de la Recherche Médicale, Caen, France

Inflammatory cell trafficking into the brain complicates several neurological disorders including multiple sclerosis. Normally, reliable brain functioning is maintained and controlled by the blood-brain barrier (BBB), which is essential to restrict the entry of potentially harmful molecules and cells from the blood into the brain. The BBB is a selective barrier formed by dedicated brain endothelial cells and dependent on the presence of intracellular tight junctions. In multiple sclerosis, a severe dysfunction of the BBB is observed, which is key to monocyte infiltration and inflammation in the brain. Proteolytic activity has been associated with these inflammatory processes in the brain. Our studies in plasma of rats indicated that the extracellular protease tissue-type plasminogen activator (tPA) correlates with the clinical signs of experimental allergic encephalomyelitis, a rat model of multiple sclerosis. In this study, we studied the function of the tPA during diapedesis of monocytes through a rat and human brain endothelial barrier. Monocyte-brain endothelial cell coculture experiments showed that monocytes induce the release of tPA by brain endothelial cells, which subsequently activates the signal transduction protein extracellular signal related kinase (ERK1/2), both involved in monocyte diapedesis. Importantly, live imaging and immunoblot analyses of rat brain endothelial cells revealed that tPA and ERK1/2 control the breakdown of the tight junction protein occludin. These studies identify tPA as a novel and relevant pathological mediator of neuroinflammation and provide a potential mechanism for this.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Netherlands Organization of Scientific Research (to A.R., G.K., and H.E.d.V.; Grant 016.046.314), MS Research Foundation (to H.E.d.V.; Grant 00-427), and Senter Novum (to S.M.A.v.d.P.).

² Address correspondence and reprint requests to Dr. Arie Reijerkerk, Neuroimmunology Research Group, Molecular Cell Biology and Immunology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: a.reijerkerk{at}vumc.nl

³ Abbreviations used in this paper: MS, multiple sclerosis; BBB, blood-brain barrier; tPA, tissue-type plasminogen activator; EAE, experimental allergic encephalomyelitis; ROS, reactive oxygen species; NOS, NO synthase.