title: Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1.
abstract: Leukocyte transmigration is mediated by endothelial cell (EC) junctional molecules, but the associated mechanisms remain unclear. Here we investigate how intercellular adhesion molecule-2 (ICAM-2), junctional adhesion molecule-A (JAM-A), and platelet endothelial cell adhesion molecule (PECAM-1) mediate neutrophil transmigration in a stimulus-dependent manner (eg, as induced by interleukin-1beta [IL-1beta] but not tumor necrosis factor-alpha [TNF-alpha]), and demonstrate their ability to act in sequence. Using a cell-transfer technique, transmigration responses of wild-type and TNF-alpha p55/p75 receptor-deficient leukocytes (TNFR(-/-)) through mouse cremasteric venules were quantified by fluorescence intravital microscopy. Whereas wild-type leukocytes showed a normal transmigration response to TNF-alpha in ICAM-2(-/-), JAM-A(-/-), and PECAM-1(-/-) recipient mice, TNFR(-/-) leukocytes exhibited a reduced transmigration response. Hence, when the ability of TNF-alpha to directly stimulate neutrophils is blocked, TNF-alpha-induced neutrophil transmigration is rendered dependent on ICAM-2, JAM-A, and PECAM-1, suggesting that the stimulus-dependent role of these molecules is governed by the target cell being activated. Furthermore, analysis of the site of arrest of neutrophils in inflamed tissues from ICAM-2(-/-), JAM-A(-/-), and PECAM-1(-/-) mice demonstrated that these molecules act sequentially to mediate transmigration. Collectively, the findings provide novel insights into the mechanisms of action of key molecules implicated in leukocyte transmigration.
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, William Harvey Research Institute, London, United Kingdom.
authors.forename: Abigail
authors.initials: A
authors.lastname: Woodfin
authors.forename: Mathieu-Benoit
authors.initials: MB
authors.lastname: Voisin
authors.forename: Beat A
authors.initials: BA
authors.lastname: Imhof
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Sussan
authors.initials: S
authors.lastname: Nourshargh
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; C498686:F11r protein, mouse; C480027:ICAM-2 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha