Favret Jacob, Maulik Malabika, Masoom Rayan, Kushwaha Meghana, Thompson Devin, Browne Richard, Shin Daesung
Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14214, USA.
Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14203, USA.
Sci Rep. 2024 Dec 30;14(1):31822. doi: 10.1038/s41598-024-82927-1.
Lipocalin-2 (LCN2) is an acute-phase secretory molecule significantly upregulated in various neuroinflammatory and demyelinating conditions. Krabbe disease (KD) is a neurodegenerative lysosomal disorder caused by a galactosylceramidase (GALC) deficiency, accumulating cytotoxic psychosine in nervous systems, and subsequent neuroinflammation. Here, we show that LCN2 is highly overexpressed in GALC-deficient astrocytes. To further understand if the elevated LCN2 is critical for KD progression, we globally deleted Lcn2 in the Galc-knockout (KO) mouse model. Interestingly, the Galc and Lcn2 double KO mice showed dramatically reduced neuroinflammation including gliosis. Pro-inflammatory cytokines such as TNF-α, MMP3, and MCP-1 were significantly downregulated in the brain of the double KO mice compared to Galc-KO. In addition, the ablation of Lcn2 marginally increased the survival and attenuated disease progression in Galc-KO mice. However, the accumulation of psychosine was not altered in the brain by LCN2 deficiency. Our findings suggest that the upregulation of LCN2 is crucial for the aggravation of neuroinflammation in a mouse model of Krabbe disease.
脂联素-2（LCN2）是一种急性期分泌分子，在各种神经炎症和脱髓鞘疾病中显著上调。克拉伯病（KD）是一种神经退行性溶酶体疾病，由半乳糖神经酰胺酶（GALC）缺乏引起，导致细胞毒性精神鞘氨醇在神经系统中蓄积，进而引发神经炎症。在此，我们表明LCN2在GALC缺乏的星形胶质细胞中高度过表达。为了进一步了解LCN2升高对KD进展是否至关重要，我们在Galc基因敲除（KO）小鼠模型中整体敲除了Lcn2。有趣的是，Galc和Lcn2双敲除小鼠的神经炎症包括胶质增生显著减轻。与Galc-KO小鼠相比，双敲除小鼠脑中促炎细胞因子如TNF-α、MMP3和MCP-1显著下调。此外，敲除Lcn2略微提高了Galc-KO小鼠的存活率并减缓了疾病进展。然而，LCN2缺乏并未改变脑中精神鞘氨醇的蓄积。我们的研究结果表明，LCN2的上调对于克拉伯病小鼠模型中神经炎症的加重至关重要。
