Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia
Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia
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DOI：
10.1038/s41593-021-00801-z
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发表时间：
2021-02-18
影响因子：
25
通讯作者：
Yong, V. Wee
中科院分区：
文献类型：
--
作者：
Dong, Yifei;D'Mello, Charlotte;Yong, V. Wee
多发性硬化症（MS）中发生的神经变性有助于残疾的进展。因此，重要的是要确定和中和的机制，促进神经退行性疾病在MS。在这里，我们报告氧化磷脂酰胆碱（OxPC）发现在MS病变，以前确定为氧化应激的终产物标志物，是神经退行性疾病的有力驱动程序。培养的神经元和少突胶质细胞被OxPCs杀死，而小胶质细胞可以改善这种情况。注射OxPC后，小鼠脊髓出现局灶性脱髓鞘病变，伴有明显的轴突丢失。在OxPC病变中积累的小胶质细胞的消耗加剧了神经变性。损伤脊髓的单细胞RNA测序鉴定了响应OxPC沉积的TREM 2（高）小鼠小胶质细胞的独特子集。在人MS病变中检测到TREM 2，并且TREM 2（-/-）小鼠表现出恶化的OxPC病变。这些结果将OxPC鉴定为有效的神经毒素，并表明通过TREM 2增强小胶质细胞介导的OxPC清除可以帮助预防MS中的神经变性。
Neurodegeneration occurring in multiple sclerosis (MS) contributes to the progression of disability. It is therefore important to identify and neutralize the mechanisms that promote neurodegeneration in MS. Here, we report that oxidized phosphatidylcholines (OxPCs) found in MS lesions, previously identified as end-product markers of oxidative stress, are potent drivers of neurodegeneration. Cultured neurons and oligodendrocytes were killed by OxPCs, and this was ameliorated by microglia. After OxPC injection, mouse spinal cords developed focal demyelinating lesions with prominent axonal loss. The depletion of microglia that accumulated in OxPC lesions exacerbated neurodegeneration. Single-cell RNA sequencing of lesioned spinal cords identified unique subsets of TREM2(high) mouse microglia responding to OxPC deposition. TREM2 was detected in human MS lesions, and TREM2(-/-) mice exhibited worsened OxPC lesions. These results identify OxPCs as potent neurotoxins and suggest that enhancing microglia-mediated OxPC clearance via TREM2 could help prevent neurodegeneration in MS.