Howell John Aaron, Larochelle Jonathan, Gunraj Rachel E, Stansbury Sofia M, Liu Lei, Yang Changjun, Candelario-Jalil Eduardo
University of Florida, Department of Neuroscience, United States.
University of Florida McKnight Brain Institute, United States.
Aging Brain. 2025 Mar 29;7:100135. doi: 10.1016/j.nbas.2025.100135. eCollection 2025.
Besides the loss of blood and oxygen reaching the ischemic tissue, many secondary effects of ischemic stroke can cause additional tissue damage, including inflammation, oxidative stress, and proteomic disturbances. Receptor-interacting serine/threonine kinase 2 (RIPK2) is an important mediator in the post-stroke inflammatory cascade that responds to signals and molecular patterns released by dead or dying cells in the ischemic area. We hypothesize that RIPK2 signaling worsens injury and neurological recovery post-stroke and that global deletion of is protective following ischemic stroke in aged mice. Aged (18-24 months) male mice were subjected to permanent middle cerebral artery occlusion (pMCAO). Vertical grid, weight grip, and open field were conducted at baseline and on days 1, 2, 3, 8, 15, and 22 post-stroke. Cognitive tests (novel object recognition and Y-maze) were performed at baseline and day 28 post-stroke. Infarct size was measured using cresyl violet staining, and reactive gliosis was measured using Iba1 and GFAP staining at day 28 post-stroke. Global deletion of ( ) in aged mice resulted in smaller infarct volume and improved performance on vertical grid and weight grip tests compared to aged wildtype (WT) mice. Additionally, aged mice had less Iba1 staining in the ipsilateral cortex than the aged WT control mice. This study further elucidates the role of RIPK2 signaling in the ischemic cascade and expands our knowledge of RIPK2 in stroke to aged mice. These results support the hypothesis that RIPK2 signaling worsens injury post-stroke and may be an attractive candidate for therapeutic intervention.
除了流向缺血组织的血液和氧气流失外，缺血性中风的许多继发效应会导致额外的组织损伤，包括炎症、氧化应激和蛋白质组紊乱。受体相互作用丝氨酸/苏氨酸激酶2（RIPK2）是中风后炎症级联反应中的重要介质，可对缺血区域中死亡或濒死细胞释放的信号和分子模式做出反应。我们假设RIPK2信号会加重中风后的损伤和神经恢复，并且在老年小鼠缺血性中风后全局缺失该信号具有保护作用。对18至24个月大的雄性小鼠进行永久性大脑中动脉闭塞（pMCAO）。在基线以及中风后的第1、2、3、8、15和22天进行垂直网格、握力和旷场测试。在基线和中风后第28天进行认知测试（新物体识别和Y迷宫）。在中风后第28天，使用甲酚紫染色测量梗死体积，使用Iba1和GFAP染色测量反应性胶质增生。与老年野生型（WT）小鼠相比，老年小鼠中全局缺失该信号导致梗死体积更小，并且在垂直网格和握力测试中的表现有所改善。此外，与老年WT对照小鼠相比，老年缺失该信号的小鼠同侧皮质中的Iba1染色更少。这项研究进一步阐明了RIPK2信号在缺血级联反应中的作用，并扩展了我们对老年小鼠中风中RIPK2的认识。这些结果支持了RIPK2信号会加重中风后损伤的假设，并且可能是治疗干预的一个有吸引力的候选靶点。
