作为中枢神经系统中的常驻免疫细胞，小胶质细胞表现出“致敏”或“启动”表型，在衰老的大脑中具有营养不良的形态和失调的功能。尽管研究已经证明了老年小胶质细胞在几种神经系统疾病中的炎症特征，但这个问题在中风中很大程度上是不确定的。因此，本研究调查了小胶质细胞的引发和再生对老年小鼠缺血后脑损伤的影响。我们通过药物给药和撤回集落刺激因子 1 受体 (CSF1R) 抑制剂 PLX3397，用新再生的小胶质细胞替换了已引发的小胶质细胞。此外，我们在大脑中动脉闭塞（MCAO）小鼠模型中进行了一系列行为测试和流式细胞术，以研究小胶质细胞替代对老年大脑缺血性损伤的影响。随着 MCAO 小鼠中小胶质细胞的消耗和随后的重新增殖，老年小鼠的小胶质细胞替代改善了神经功能并减少了脑梗塞。这种保护作用伴随着浸润大脑的外周免疫细胞的减少。我们发现，重新填充的小胶质细胞表达升高的神经保护因子（包括分化簇 206、转化生长因子-β 和白细胞介素 10），并减少炎症标记物的表达（包括分化簇 86、白细胞介素 6 和肿瘤坏死因子 α） ）。此外，小胶质细胞替代可以保护血脑屏障并减轻接受 60 分钟 MCAO 的老年小鼠的神经元死亡。这些结果表明，替换衰老大脑中的小胶质细胞可能会减轻脑损伤和神经炎症，从而减轻缺血性脑损伤。因此，针对小胶质细胞可能是缺血性中风的一种有前景的治疗策略。版权所有 © 2024 Elsevier B.V. 保留所有权利。

As the resident immune cells in the central nervous system, microglia exhibit a 'sensitized' or 'primed' phenotype with dystrophic morphology and dysregulated functions in aged brains. Although studies have demonstrated the inflammatory profile of aged microglia in several neurological diseases, this issue is largely uncertain in stroke. Consequently, this study investigated the effects of primed and repopulated microglia on post-ischemic brain injury in aged mice. We replaced primed microglia with newly repopulated microglia through pharmacological administration and withdrawal of the colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397. Further, we performed a series of behavioral tests and flow cytometry in mouse models of middle cerebral artery occlusion (MCAO) to study the effects of microglial replacement on ischemic injury in the aged brain. With depletion and subsequent repopulation of microglia in MCAO mice, microglial replacement in aged mice improved neurological function and decreased brain infarction. This protective effect was accompanied by the reduction of peripheral immune cells infiltrating into brains. We showed that the repopulated microglia expressed elevated neuroprotective factors (including Cluster of Differentiation 206, transforming growth factor-β, and interleukin-10) and diminished expression of inflammatory markers (including Cluster of Differentiation 86, interleukin-6, and tumor necrosis factor α). Moreover, microglial replacement protected the blood-brain barrier and relieved neuronal death in aged mice subjected to 60 min of MCAO. These results imply that the replacement of microglia in the aged brain may alleviate brain damage and neuroinflammation, and therefore, ischemic brain damage. Thus, targeting microglia could be a promising therapeutic strategy for ischemic stroke.Copyright © 2024 Elsevier B.V. All rights reserved.