Lipocalin-2 regulates astrocyte-oligodendrocyte interaction to drive post-stroke secondary demyelination
Zhenqian Huang, Xiaohao Zhang, Ying Zhao, Mingming Zha, Min Wu, Di Wang, Qiushi Lv, Yunzi Li, Jingwen Qi, Jie Gao, Ruidong Ye, Weixin Yuan, Junxian Shen, Wusheng Zhu, Xinfeng Liu, Yi Xie
Abstract
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.