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: Nikola Sladojevic, Svetlana M Stamatovic, Richard F Keep, Jamison J Grailer, J Vidya Sarma, Peter A Ward, Anuska V Andjelkovic
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 67 Pg. 57-70 (Jul 2014) ISSN: 1095-953X [Electronic] United States
• PMID: 24657919 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Junctional Adhesion Molecule A
• Lymphocyte Function-Associated Antigen-1

Topics

• Animals
• Brain (metabolism)
• Brain Ischemia (metabolism, physiopathology)
• Cell Movement
• Encephalitis (metabolism, physiopathology)
• Infarction, Middle Cerebral Artery (metabolism)
• Junctional Adhesion Molecule A (antagonists & inhibitors)
• Leukocytes (physiology)
• Lymphocyte Function-Associated Antigen-1 (metabolism)
• Mice
• Reperfusion Injury (metabolism, physiopathology)