Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
Benaroya Research Institute, Seattle, United States.
Nat Commun. 2022 May 4;13(1):2445. doi: 10.1038/s41467-022-30032-0.
Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2:MAPT mice illuminating newly formed GFP oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS.
多发性硬化症（MS）中的髓鞘再生失败导致残疾进展。这种修复不足是由于神经炎症和抑制剂的沉积引起的，包括软骨素硫酸盐蛋白聚糖（CSPGs）。哪种 CSPG 成员具有抑制修复作用或改变局部炎症以加剧损伤尚不清楚。在这里，我们将 MS 病变中高表达的 versican-V1 与少突胶质前体细胞（OPC）的缺陷相关联，并强调其在实验性自身免疫性脑脊髓炎（EAE）病变中 CSPG 成员中的选择性上调，这些病变模拟 MS。在培养物中，纯化的 versican-V1 抑制少突胶质前体细胞（OPC）并促进辅助性 T 细胞 17（Th17）极化。暴露于 versican-V1 的 Th17 细胞对 OPC 特别有毒。在 NG2：MAPT 小鼠中，新形成的 GFP 少突胶质细胞/髓鞘被照亮，在 EAE 高峰时用 difluorosamine（全乙酰化，4,4-二氟-N-乙酰氨基葡萄糖）治疗可降低病变中的 versican-V1 和 Th17 频率，同时增强 GFP 图谱。我们认为，病变中升高的 versican-V1 直接阻碍 OPC，同时通过升高局部 Th17 细胞毒性神经炎症间接抑制髓鞘再生。我们提出降低 CSPG 的药物可能是 MS 的潜在双重修复和免疫调节治疗方法。
