Feng Shuai, Li Juanji, Liu Tingting, Huang Shiqi, Chen Xiangliang, Liu Shen, Zhou Junshan, Zhao Hongdong, Hong Ye
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
Department of Neurology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China.
Neural Regen Res. 2025 Feb 1;20(2):491-502. doi: 10.4103/NRR.NRR-D-23-01263. Epub 2024 Apr 16.
JOURNAL/nrgr/04.03/01300535-202502000-00027/figure1/v/2024-05-28T214302Z/r/image-tiff Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury. Low-density lipoprotein receptor, a classic cholesterol regulatory receptor, has been found to inhibit NLR family pyrin domain containing protein 3 (NLRP3) inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer's disease. However, little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke. To address this issue in the present study, we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models. First, we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis. We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation. Second, we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus. Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype. Finally, we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin, an NLRP3 agonist, restored the neurotoxic astrocyte phenotype. These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
《期刊》/nrgr/04.03/01300535 - 202502000 - 00027/图1/v/2024 - 05 - 28T214302Z/图像 - 标签图像文件格式 神经毒性星形胶质细胞是减轻脑缺血/再灌注损伤的一个有前景的治疗靶点。低密度脂蛋白受体是一种经典的胆固醇调节受体，已发现在缺血性中风后它可抑制神经元中含NLR家族吡啉结构域蛋白3（NLRP3）炎性小体的激活，并在阿尔茨海默病患者中抑制小胶质细胞和星形胶质细胞的激活。然而，关于低密度脂蛋白受体对缺血性中风中星形胶质细胞激活的影响知之甚少。为在本研究中解决这一问题，我们研究了低密度脂蛋白受体在缺血性中风模型中调节星形胶质细胞极化的机制。首先，我们通过免疫荧光染色和蛋白质印迹分析检测了星形胶质细胞中低密度脂蛋白受体的表达。我们观察到大脑中动脉闭塞再灌注和氧糖剥夺/复氧后低密度脂蛋白受体显著下调。其次，我们使用星形胶质细胞特异性腺相关病毒诱导低密度脂蛋白受体在星形胶质细胞中的特异性过表达。星形胶质细胞中低密度脂蛋白受体的过表达改善了大脑中动脉闭塞小鼠的神经功能结局，并使神经毒性星形胶质细胞逆转以产生神经保护表型。最后，我们发现低密度脂蛋白受体的过表达抑制了氧糖剥夺/复氧损伤的星形胶质细胞中NLRP3炎性小体的激活，并且添加NLRP3激动剂尼日利亚菌素可恢复神经毒性星形胶质细胞表型。这些发现表明，低密度脂蛋白受体可抑制NLRP3介导的星形胶质细胞神经毒性极化，并且增加星形胶质细胞中的低密度脂蛋白受体可能代表一种治疗脑缺血性中风的新策略。
