title: Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury.
abstract: Proinflammatory mediators trigger intensive postischemic inflammatory remodeling of the blood-brain barrier (BBB) including extensive brain endothelial cell surface and junctional complex changes. Junctional adhesion molecule-A (JAM-A) is a component of the brain endothelial junctional complex with dual roles: paracellular route occlusion and regulating leukocyte docking and migration. The current study examined the contribution of JAM-A to the regulation of leukocyte (neutrophils and monocytes/macrophages) infiltration and the postischemic inflammatory response in brain ischemia/reperfusion (I/R injury). Brain I/R injury was induced by transient middle cerebral artery occlusion (MCAO) for 30min in mice followed by reperfusion for 0-5days, during which time JAM-A antagonist peptide (JAM-Ap) was administered. The peptide, which inhibits JAM-A/leukocyte interaction by blocking the interaction of the C2 domain of JAM-A with LFA on neutrophils and monocytes/macrophages, attenuated I/R-induced neutrophil and monocyte infiltration into brain parenchyma. Consequently, mice treated with JAM-A peptide during reperfusion had reduced expression (~3-fold) of inflammatory mediators in the ischemic penumbra, reduced infarct size (94±39 vs 211±38mm3) and significantly improved neurological score. BBB hyperpermeability was also reduced. Collectively, these results indicate that JAM-A has a prominent role in regulating leukocyte infiltration after brain I/R injury and could be a new target in limiting post-ischemic inflammation.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Nikola
authors.initials: N
authors.lastname: Sladojevic
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Stamatovic
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jamison J
authors.initials: JJ
authors.lastname: Grailer
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: J Vidya
authors.initials: JV
authors.lastname: Sarma
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: anuskaa@med.umich.edu.
authors.forename: Anuska V
authors.initials: AV
authors.lastname: Andjelkovic
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002465:Cell Movement; D004660:Encephalitis / Q000378:metabolism* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D062745:Junctional Adhesion Molecule A / Q000037:antagonists & inhibitors*; D007962:Leukocytes / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D062745:Junctional Adhesion Molecule A; D016169:Lymphocyte Function-Associated Antigen-1
keywords: Blood–brain barrier; Inflammation; JAM-A; Stroke; Tight junctions