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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2852-2861.
Prepublished online as a Blood First Edition Paper on December 9, 2004; DOI 10.1182/blood-2004-09-3606.


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IMMUNOBIOLOGY

Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation

Olga Barreiro, María Yáñez-Mó, Mónica Sala-Valdés, María Dolores Gutiérrez-López, Susana Ovalle, Adrian Higginbottom, Peter N. Monk, Carlos Cabañas, and Francisco Sánchez-Madrid

From the Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain; Instituto de Farmacología y Toxicología, Consejo Superior de Investigaciones Científicas–Universidad Complutense de Madrid (CSIC-UCM), Facultad de Medicina, Universidad Complutense, Madrid, Spain; and Department of Academic Neurology, The Medical School, University of Sheffield, United Kingdom.

Tetraspanins associate with several transmembrane proteins forming microdomains involved in intercellular adhesion and migration. Here, we show that endothelial tetraspanins relocalize to the contact site with transmigrating leukocytes and associate laterally with both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Alteration of endothelial tetraspanin microdomains by CD9–large extracellular loop (LEL)–glutathione S–transferase (GST) peptides or CD9/CD151 siRNA oligonucleotides interfered with ICAM-1 and VCAM-1 function, preventing lymphocyte transendothelial migration and increasing lymphocyte detachment under shear flow. Heterotypic intercellular adhesion mediated by VCAM-1 or ICAM-1 was augmented when expressed exogenously in the appropriate tetraspanin environment. Therefore, tetraspanin microdomains have a crucial role in the proper adhesive function of ICAM-1 and VCAM-1 during leukocyte adhesion and transendothelial migration.


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