Sladojevic Nikola, Stamatovic Svetlana M, Keep Richard F, Grailer Jamison J, Sarma J Vidya, Ward Peter A, Andjelkovic Anuska V
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; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Neurobiol Dis. 2014 Jul;67:57-70. doi: 10.1016/j.nbd.2014.03.010. Epub 2014 Mar 21.
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.
促炎介质引发血脑屏障（BBB）缺血后强烈的炎症重塑，包括广泛的脑内皮细胞表面和连接复合体变化。连接黏附分子A（JAM-A）是脑内皮连接复合体的一个组成部分，具有双重作用：封闭细胞旁通道以及调节白细胞停靠和迁移。本研究检测了JAM-A在脑缺血/再灌注（I/R损伤）中对白细胞（中性粒细胞和单核细胞/巨噬细胞）浸润调节及缺血后炎症反应的作用。通过短暂阻断小鼠大脑中动脉（MCAO）30分钟，随后再灌注0-5天诱导脑I/R损伤，在此期间给予JAM-A拮抗剂肽（JAM-Ap）。该肽通过阻断JAM-A的C2结构域与中性粒细胞和单核细胞/巨噬细胞上的淋巴细胞功能相关抗原-1（LFA）的相互作用来抑制JAM-A/白细胞相互作用，减轻了I/R诱导的中性粒细胞和单核细胞浸润到脑实质中。因此，在再灌注期间用JAM-A肽治疗的小鼠，缺血半暗带中炎症介质的表达降低（约3倍），梗死体积减小（94±39 vs 211±38mm3），神经功能评分显著改善。血脑屏障的高通透性也降低了。总体而言，这些结果表明JAM-A在脑I/R损伤后调节白细胞浸润中起重要作用，可能是限制缺血后炎症的新靶点。
