title: Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, 91 Riding House Street, London W1W 7BS, UK.
authors.forename: Jaime
authors.initials: J
authors.lastname: Millán
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hewlett
authors.forename: Matthew
authors.initials: M
authors.lastname: Glyn
authors.forename: Derek
authors.initials: D
authors.lastname: Toomre
authors.forename: Peter
authors.initials: P
authors.lastname: Clark
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
mesh_terms: D000199:Actins / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D021941:Caveolae / Q000502:physiology* / Q000648:ultrastructure; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D022081:Cell Surface Extensions / Q000502:physiology; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology*; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D011940:Receptor Aggregation / Q000502:physiology; D022502:Stress Fibers / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; C495540:CAV1 protein, human; D051242:Caveolin 1; D019040:E-Selectin; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1