Huang Zhenqian, Zhang Xiaohao, Zhao Ying, Zha Mingming, Wu Min, Wang Di, Lv Qiushi, Li Yunzi, Qi Jingwen, Gao Jie, Ye Ruidong, Yuan Weixin, Shen Junxian, Zhu Wusheng, Liu Xinfeng, Xie Yi
Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China.
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Cell Rep. 2025 Jul 22;44(7):115899. doi: 10.1016/j.celrep.2025.115899. Epub 2025 Jun 21.
Secondary demyelination worsens outcomes after cerebral infarction, but astrocyte-oligodendrocyte interactions in this process remain unclear. Using distal middle cerebral artery occlusion (dMCAO) in mice, we show that lipocalin-2 (LCN2), partially diffusing from the infarct-adjacent corpus callosum, is transcriptionally and translationally upregulated in reactive astrocytes of the contralateral corpus callosum by 7 days post-injury. At upstream levels, PERK-orchestrated endoplasmic reticulum stress drives contralateral astrocytic activation and autonomous LCN2 synthesis. Subsequent LCN2 uptake by mature oligodendrocytes leads to process degeneration and cell apoptosis. Astrocyte-specific Lcn2 ablation reduces oligodendrocyte loss, demyelination, and cognitive deficits post-dMCAO, effects reversed by astrocyte-specific LCN2 re-expression. Mechanistically, such LCN2-dependent myelin damage might involve a physical interaction with oligodendrocyte low-density lipoprotein receptor-related protein 2 (LRP2), which subsequently activates the JNK3 pathway. Specific Lrp2 knockdown mitigates LCN2-induced oligodendrocyte damage. Our findings demonstrate that reactive astrocytes regulate post-stroke secondary demyelination through LCN2-LRP2 signaling, revealing an intercellular pathogenic axis.
继发性脱髓鞘会使脑梗死的预后恶化，但这一过程中星形胶质细胞与少突胶质细胞之间的相互作用仍不清楚。利用小鼠大脑中动脉远端闭塞（dMCAO）模型，我们发现，损伤后7天，从梗死灶相邻的胼胝体部分扩散而来的脂质运载蛋白2（LCN2）在对侧胼胝体的反应性星形胶质细胞中转录和翻译水平均上调。在上游水平，PERK介导的内质网应激驱动对侧星形胶质细胞活化和LCN2自主合成。随后，成熟少突胶质细胞摄取LCN2会导致其突起退化和细胞凋亡。星形胶质细胞特异性敲除Lcn2可减少dMCAO后的少突胶质细胞丢失、脱髓鞘和认知缺陷，而星形胶质细胞特异性重新表达LCN2可逆转这些效应。从机制上讲，这种依赖LCN2的髓鞘损伤可能涉及与少突胶质细胞低密度脂蛋白受体相关蛋白2（LRP2）的物理相互作用，进而激活JNK3通路。特异性敲低Lrp2可减轻LCN2诱导的少突胶质细胞损伤。我们的研究结果表明，反应性星形胶质细胞通过LCN2-LRP2信号传导调节中风后的继发性脱髓鞘，揭示了一条细胞间致病轴。
