Laboratory for Experimental Brain Research, Department of Clinical Sciences, Division of Neurosurgery, Lund University, BMC A13, 22184 Lund, Sweden.
Department of Psychiatry and Neuroscience, Laval University, Le Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, 2601, de la Canardière, Québec G1J 2G3, Canada.
Neurobiol Dis. 2014 Jun;66:66-73. doi: 10.1016/j.nbd.2014.02.010. Epub 2014 Mar 6.
Post-ischemic inflammation plays an important role in the evolution of brain injury, recovery and repair after stroke. Housing rodents in an enriched environment provides multisensory stimulation to the brain and enhances functional recovery after experimental stroke, also depressing the release of cytokines and chemokines in the peri-infarct. In order to identify targets for late stroke treatment, we studied the dynamics of inflammation and the contribution of resident Toll-like receptor 2 (TLR2) expressing microglia cells. We took advantage of the biophotonic/bioluminescent imaging technique using the reporter mouse-expressing luciferase and GFP reporter genes under transcriptional control of the murine TLR2 promoter (TLR2-luc/GFP mice) for non-invasive in vivo analysis of TLR2 activation/response in photothrombotic stroke after differential housing. Real-time imaging at 1day after stroke, revealed up-regulation of TLR2 in response to photothrombotic stroke that subsequently declined over time of recovery (14days). The inflammatory response was persistently down-regulated within days of enriched housing, enhancing recovery of lost sensori-motor function in TLR2-luc mice without affecting infarct size. The number of YM1-expressing microglia in the peri-infarct and areas remote from the infarct was also markedly attenuated. Using a live imaging approach, we demonstrate that multisensory stimulation rapidly, persistently and generally attenuates brain inflammation after experimental stroke, reducing the TLR2 response and leading to improved neurological outcome. TLR2-expressing microglia cells may provide targets for new stroke therapeutics.
缺血后炎症在中风后脑损伤的演变、恢复和修复中起着重要作用。将啮齿动物饲养在丰富的环境中可以为大脑提供多感官刺激，并增强实验性中风后的功能恢复，同时还可以抑制梗塞周围细胞因子和趋化因子的释放。为了确定中风后晚期治疗的靶点，我们研究了炎症的动态变化以及表达 Toll 样受体 2 (TLR2) 的固有小胶质细胞的作用。我们利用生物发光/生物发光成像技术，利用表达荧光素酶和 GFP 报告基因的报告鼠，这些报告基因受鼠 TLR2 启动子的转录控制（TLR2-luc/GFP 鼠），对光血栓性中风后不同环境下 TLR2 的激活/反应进行非侵入性体内分析。中风后 1 天的实时成像显示，TLR2 对光血栓性中风的反应上调，随后随着恢复时间的延长而下降（14 天）。在丰富环境的几天内，炎症反应持续下调，增强了 TLR2-luc 小鼠失去的感觉运动功能的恢复，而不影响梗死面积。梗塞周围和远离梗塞区的 YM1 表达小胶质细胞的数量也明显减少。使用活体成像方法，我们证明了多感官刺激可迅速、持续和普遍地减轻实验性中风后的大脑炎症，降低 TLR2 反应，并导致神经功能改善。表达 TLR2 的小胶质细胞可能为新的中风治疗提供靶点。
