Article abstract
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 domains
Jaime Millán1,2, Lindsay Hewlett3, Matthew Glyn4, Derek Toomre5, Peter Clark4 & Anne J. Ridley1,2
Abstract
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.
- Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, 91 Riding House Street, London W1W 7BS, UK.
- Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
- MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.
- Leukocyte Biology, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London SW7 2AZ, UK.
- 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 to: Anne J. Ridley1,2 e-mail: anne@ludwig.ucl.ac.uk
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