Abstract
Ischemic stroke can cause secondary myelin damage in the white matter distal to the primary injury site. The contribution of astrocytes during secondary demyelination and the underlying mechanisms are unclear. Here, using a mouse of distal middle cerebral artery occlusion, we show that lipocalin-2 (LCN2), enriched in reactive astrocytes, expression increases in nonischemic areas of the corpus callosum upon injury. LCN2-expressing astrocytes acquire a phagocytic phenotype and are able to uptake myelin. Myelin removal is impaired in Lcn2−/− astrocytes. Inducing re-expression of truncated LCN2(Δ2–20) in astrocytes restores phagocytosis and leads to progressive demyelination in Lcn2−/− mice. Co-immunoprecipitation experiments show that LCN2 binds to low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. Knockdown of Lrp1 reduces LCN2-induced myelin engulfment by astrocytes and reduces demyelination. Altogether, our findings suggest that LCN2/LRP1 regulates astrocyte-mediated myelin phagocytosis in a mouse model of ischemic stroke.
Highlights
Ischemic stroke can cause secondary myelin damage in the white matter distal to the primary injury site
T2-weighted imaging (T2-WI) and diffusion-weighted imaging (DWI) further showed that the infarction was mainly restricted to the cerebral cortex with an average volume of 10.30% (Fig. 1D, E; P < 0.001)
The levels of myelinated fiber markers, including myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and neurofilament marker neurofilament 200 (NF200), were all significantly reduced after stroke (Fig. 1G, H; P < 0.001 for MBP, P = 0.0068 for MAG, P = 0.0175 for NF200), which was further verified by immunoblotting (Fig. 1I, J; both P = 0.001)
Summary
Ischemic stroke can cause secondary myelin damage in the white matter distal to the primary injury site. Reactive astrocytes can exert phagocytic effects to clear a variety of debris in the brain following ischemic injury[5]. These cells are mainly observed in the penumbra region during the later phase after injury[5]. Whether the reactive astrocytes can phagocytose myelin debris following cortical infarction and whether this myelin phagocytosis is associated with demyelination remain largely unclear. Low-density lipoprotein receptor-related protein 1 (LRP1) is required for LCN2-induced myelin phagocytosis by astrocytes. These findings collectively suggest that hypertrophic astrocytes can phagocytose myelin after cortical ischemia and promote demyelination through the LCN2/ LRP1 pathway
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