title: Junctional adhesion molecule-A deficiency increases hepatic ischemia-reperfusion injury despite reduction of neutrophil transendothelial migration.
abstract: The endothelial receptors that control leukocyte transmigration in the postischemic liver are not identified. We investigated the role of junctional adhesion molecule-A (JAM-A), a receptor expressed in endothelial tight junctions, leukocytes, and platelets, for leukocyte transmigration during hepatic ischemia-reperfusion (I/R) in vivo. We show that JAM-A is up-regulated in hepatic venular endothelium during reperfusion. I/R-induced neutrophil transmigration was attenuated in both JAM-A-/- and endothelial JAM-A-/- mice as well as in mice treated with an anti-JAM-A antibody, whereas transmigration of T cells was JAM-A independent. Postischemic leukocyte rolling remained unaffected in JAM-A-/- and endothelial JAM-A-/- mice, whereas intravascular leukocyte adherence was increased. The extent of interactions of JAM-A-/- platelets with the postischemic endothelium was comparable with that of JAM-A+/+ platelets. The I/R-induced increase in the activity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and sinusoidal perfusion failure was not reduced in JAM-A-/- mice, while the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive hepatocytes was significantly higher. Thus, we show for the first time that JAM-A is up-regulated in hepatic venules and serves as an endothelial receptor of neutrophil transmigration, but it does not mediate leukocyte rolling, adhesion, or platelet-endothelial cell interactions. JAM-A deficiency does not reduce I/R-induced microvascular and hepatocellular necrotic injury, but increases hepatocyte apoptosis, despite attenuation of neutrophil infiltration.
authors.affiliation: Institute for Surgical Research, Ludwig-Maximilians-University of Munich, Marchioninistr. 27, D-81377 Munich, Germany. andrej.khandoga@med.uni-muenchen.de
authors.forename: Andrej
authors.initials: A
authors.lastname: Khandoga
authors.forename: Julia S
authors.initials: JS
authors.lastname: Kessler
authors.forename: Herbert
authors.initials: H
authors.lastname: Meissner
authors.forename: Marc
authors.initials: M
authors.lastname: Hanschen
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Motoike
authors.forename: Georg
authors.initials: G
authors.lastname: Enders
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.forename: Fritz
authors.initials: F
authors.lastname: Krombach
mesh_terms: D000818:Animals; D001483:Base Sequence; D001792:Blood Platelets / Q000473:pathology / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression; D036904:Leukocyte Rolling / Q000502:physiology; D008099:Liver / Q000098:blood supply / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology* / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015427:Reperfusion Injury / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology
chemical_list: D015815:Cell Adhesion Molecules; D018076:DNA, Complementary; C498686:F11r protein, mouse; D011956:Receptors, Cell Surface