Nature Cell Biology 8, 113 - 123 (2006)
Published online: 22 January 2006; | doi:10.1038/ncb1356
Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domainsJaime Millán1, 2, Lindsay Hewlett3, Matthew Glyn4, Derek Toomre5, Peter Clark4
& Anne J. Ridley1, 21
Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, 91 Riding House Street, London W1W 7BS, UK. 2
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK. 3
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK. 4
Leukocyte Biology, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London SW7 2AZ, UK. 5
Ludwig Institute for Cancer Research, Department of Cell Biology, Yale University School of Medicine, 333 Cedar St., PO Box 208002, New Haven, 06520–8002 CT, USA.
Correspondence should be addressed to Anne J. Ridley anne@ludwig.ucl.ac.uk During inflammation, leukocytes bind to the adhesion receptors ICAM-1 and VCAM-1 on the endothelial surface before undergoing transendothelial migration, also called diapedesis. ICAM-1 is also involved in transendothelial migration, independently of its role in adhesion, but the molecular basis of this function is poorly understood. Here we demonstrate that, following clustering, apical ICAM-1 translocated to caveolin-rich membrane domains close to the ends of actin stress fibres. In these F-actin-rich areas, ICAM-1 was internalized and transcytosed to the basal plasma membrane through caveolae. Human T-lymphocytes extended pseudopodia into endothelial cells in caveolin- and F-actin-enriched areas, induced local translocation of ICAM-1 and caveolin-1 to the endothelial basal membrane and transmigrated through transcellular passages formed by a ring of F-actin and caveolae. Reduction of caveolin-1 levels using RNA interference (RNAi) specifically decreased lymphocyte transcellular transmigration. We propose that the translocation of ICAM-1 to caveola- and F-actin-rich domains links the sequential steps of lymphocyte adhesion and transendothelial migration and facilitates lymphocyte migration through endothelial cells from capillaries into surrounding tissue.
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