Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury

• Published in: Neurobiology of disease 2014-07, Vol.67, p.57-70
• Main Authors: Sladojevic, Nikola, Stamatovic, Svetlana M, Keep, Richard F, Grailer, Jamison J, Sarma, J. Vidya, Ward, Peter A, Andjelkovic, Anuska V
• Format: Article
• Language: English
• Subjects: Animals; Blood–brain barrier; Brain - metabolism; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Cell Movement; Encephalitis - metabolism; Encephalitis - physiopathology; Infarction, Middle Cerebral Artery - metabolism; Inflammation; JAM-A; Junctional Adhesion Molecule A - antagonists & inhibitors; Leukocytes - physiology; Lymphocyte Function-Associated Antigen-1 - metabolism; Mice; Neurology; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Stroke; Tight junctions
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2014.03.010

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 30 min in mice followed by reperfusion for 0–5 days, 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 ± 38 mm3 ) 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.