Abstract

Targeting the immune system and thereby modulating the inflammatory response in ischemic stroke has shown promising therapeutic potential in various preclinical trials. Among those, intravenous immunoglobulins (IVIg) have moved into the focus of attention. In a murine model of experimental stroke, we explored the therapeutic potential of IVIg on the neurological outcome and the inflammatory response. Further, we used an in vitro system to assess effects of IVIg-stimulated microglia on neuronal survival. Treatment with IVIg resulted in decreased lesion sizes, without significant effects on the infiltration and activation pattern of peripheral immune cells. However, in microglia IVIg induced a switch towards an upregulation of protective polarization markers, and the ablation of microglia led to the loss of neuroprotective IVIg effects. Functionally, IVIg stimulated microglia ameliorated neuronal cell death elicited by oxygen and glucose deprivation in vitro. Notably, application of IVIg in vivo led to a comparable decrease of apoptotic neurons in the penumbra area. Although neuroprotective effects of IVIg in vivo and in vitro have been established in previous studies, we were able to show for the first time, that IVIg modulates the polarization of microglia during the pathogenesis of stroke.

中文翻译：

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静脉注射免疫球蛋白（IVIg）在小胶质细胞中诱导保护性表型，预防缺血性中风的神经元细胞死亡

摘要

在各种临床前试验中，靶向免疫系统从而调节缺血性中风的炎症反应已显示出有希望的治疗潜力。其中，静脉内免疫球蛋白（IVIg）已成为关注的焦点。在实验性中风的小鼠模型中，我们探索了IVIg对神经系统结局和炎症反应的治疗潜力。此外，我们使用了体外系统来评估IVIg刺激的小胶质细胞对神经元存活的影响。IVIg的治疗可减少病变的大小，而对周围免疫细胞的浸润和激活模式没有明显影响。然而，在小胶质细胞中，IVIg引起了向保护性极化标记上调的转换，而小胶质细胞的消融导致了神经保护性IVIg的作用丧失。在功能上 IVIg刺激了小胶质细胞改善了体外氧气和葡萄糖剥夺引起的神经元细胞死亡。值得注意的是，在体内应用IVIg导致半影区的凋亡神经元减少。尽管先前的研究已经确定了IVIg在体内和体外的神经保护作用，但我们能够首次证明IVIg在中风发病过程中调节小胶质细胞的极化。