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Endothelial and Epithelial Cell Biology Research Unit, Division of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, UK;
* Institut Cochin, Département de Biologie Cellulaire, CNRS UMR8104, INSERM567, 75014 Paris, France;
Laboratoire d’Immunologie, Faculté de Médecine, Universite de la Méditerranée, Marseille, France; and
Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow, Lanark, Scotland G12 8QQ
1Correspondence: Division of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL. E-mail: J.Greenwood{at}ucl.ac.uk
We have previously shown that the engagement of ICAM-1 on brain endothelial cells (EC) results in the propagation of EC signaling pathways that are necessary for efficient lymphocyte migration across the tight vascular barriers of the brain. Signaling via this receptor alone, however, is unlikely to explain the differential recruitment of leukocytes at different vascular beds. In this study, we investigated the role of EC heterotrimeric G-protein-mediated signaling in supporting transendothelial migration of T lymphocytes. Treatment of brain EC monolayers with pertussis toxin (PTX) resulted in ADP-ribosylation of G-protein 
subunits and inhibition (>80%) of lymphocyte migration without affecting lymphocyte adhesion. Aortic and high endothelial venule EC treated identically resulted in only partial inhibition of lymphocyte migration (<40%). Expression of ribosylation-resistant (PTX-insensitive) G-protein subunits in brain EC restored their ability to support lymphocyte migration after pretreatment with PTX. Treatment of brain EC with PTX did not inhibit ICAM-1-stimulated tyrosine phosphorylation of focal adhesion kinase, suggesting the effects of PTX in inhibiting EC facilitation of lymphocyte migration are distinct from activation of EC through ICAM-1. We conclude that a heterotrimeric G-protein-mediated signaling pathway in brain EC is essential for efficient transendothelial migration of T lymphocytes into the brain.—Adamson, P., Wilbourn, B., Etienne-Manneville, S., Calder, V., Beraud, E., Milligan, G., Couraud, P.-O., Greenwood, J. Lymphocyte trafficking through the blood–brain barrier is dependent on endothelial cell heterotrimeric G-protein signaling.
Key Words: endothelium • lymphocyte migration • EC
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