Astrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice

Ting Wan, Wusheng Zhu, Ying Zhao, Xiaohao Zhang, Ruidong Ye, Meng Zuo, Pengfei Xu, Zhenqian Huang, Chunni Zhang (), Yi Xie () and Xinfeng Liu ()
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Ting Wan: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University
Wusheng Zhu: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University
Ying Zhao: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University
Xiaohao Zhang: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University
Ruidong Ye: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University
Meng Zuo: Department of Neurology, Southwest Hospital and the First Affiliated Hospital, Army Medical University
Pengfei Xu: Stroke Center & Department of Neurology, The Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China
Zhenqian Huang: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University
Chunni Zhang: Department of Clinical Laboratory, Affiliated Jinling Hospital, Medical School of Nanjing University
Yi Xie: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University
Xinfeng Liu: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28777-9

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