title: Rapid remodeling of tight junctions during paracellular diapedesis in a human model of the blood-brain barrier.
abstract: Leukocyte transendothelial migration (TEM; diapedesis) is a critical event in immune surveillance and inflammation. Most TEM occurs at endothelial cell borders (paracellular). However, there is indirect evidence to suggest that, at the tight junctions of the blood-brain barrier (BBB), leukocytes migrate directly through the endothelial cell body (transcellular). Why leukocytes migrate through the endothelial cell body rather than the cell borders is unknown. To test the hypothesis that the tightness of endothelial cell junctions influences the pathway of diapedesis, we developed an in vitro model of the BBB that possessed 10-fold higher electrical resistance than standard culture conditions and strongly expressed the BBB tight junction proteins claudin-5 and claudin-3. We found that paracellular TEM was still the predominant pathway (≥98%) and TEM was dependent on PECAM-1 and CD99. We show that endothelial tight junctions expressing claudin-5 are dynamic and undergo rapid remodeling during TEM. Membrane from the endothelial lateral border recycling compartment is mobilized to the exact site of tight junction remodeling. This preserves the endothelial barrier by sealing the intercellular gaps with membrane and engaging the migrating leukocyte with unligated adhesion molecules (PECAM-1 and CD99) as it crosses the cell border. These findings provide new insights into leukocyte-endothelial interactions at the BBB and suggest that tight junctions are more dynamic than previously appreciated.
authors: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors: Ryan C
authors: RC
authors: Winger
authors: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors: Jennifer E
authors: JE
authors: Koblinski
authors: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan; and.
authors: Takashi
authors: T
authors: Kanda
authors: Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors: Richard M
authors: RM
authors: Ransohoff
authors: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; wamuller@northwestern.edu.
authors: William A
authors: WA
authors: Muller
mesh_terms: D000071443:12E7 Antigen; D015703:Antigens, CD / Q000276:immunology; D001812:Blood-Brain Barrier / Q000166:cytology / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology; D062465:Claudin-3 / Q000276:immunology; D062507:Claudin-5 / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D008955:Models, Cardiovascular; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D019108:Tight Junctions / Q000276:immunology*; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology*
chemical_list: D000071443:12E7 Antigen; D015703:Antigens, CD; C061828:CD99 protein, human; C568122:CLDN3 protein, human; C107466:CLDN5 protein, human; D015815:Cell Adhesion Molecules; D062465:Claudin-3; D062507:Claudin-5; D019408:Platelet Endothelial Cell Adhesion Molecule-1