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

NEUROBIOLOGY OF DISEASE

卷:67

Article

Sladojevic, Nikola¹  Stamatovic, Svetlana M.¹  Keep, Richard F.^2,3  Grailer, Jamison J.¹  Sarma, J. Vidya¹  Ward, Peter A.¹  Andjelkovic, Anuska V.^1,2 

[1] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Dept Neurosurg, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

关键词: Tight junctions;    JAM-A;    Stroke;    Inflammation;    Blood-brain barrier;   

DOI  :  10.1016/j.nbd.2014.03.010

来源: Elsevier

【 摘 要 】

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-Al 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 (similar to 3-fold) of inflammatory mediators in the ischemic penumbra, reduced infarct size (94 39 vs 211 38 mm(3)) 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. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

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