Lipocalin-2 regulates astrocyte-oligodendrocyte interaction to drive post-stroke secondary demyelination.

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.