Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans^1,2,3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state^4,5,6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define ‘microglia inflamed in MS’ (MIMS) and ‘astrocytes inflamed in MS’, glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.

多发性硬化症 (MS) 病变在形成后数月内仍未消退，并伴有持续的脱髓鞘和轴突变性，并且可通过 MRI 扫描中的顺磁性边缘在体内识别^1,2,3 。在这里，为了定义这种致残、进行性神经退行性状态的机制^4,5,6并促进新治疗药物的开发，我们使用 MRI 信息的单核 RNA 测序来分析炎症不同阶段脱髓鞘白质病变的边缘。我们发现了显着的神经胶质和免疫细胞多样性，特别是在慢性发炎的病变边缘。我们定义了“多发性硬化症中发炎的小胶质细胞”(MIMS) 和“多发性硬化症中发炎的星形胶质细胞”，这两种胶质细胞表型表明了神经退行性编程。 MIMS 转录谱与其他神经退行性疾病中小胶质细胞的转录谱重叠，表明原发性和继发性神经退行性疾病具有共同的机制，并且可以受益于类似的治疗方法。我们确定补体成分 1q (C1q) 是 MIMS 激活的关键介质，在 MS 组织中通过免疫组织化学验证，在患有实验性自身免疫性脑脊髓炎的小鼠中通过小胶质细胞特异性 C1q 消融进行遗传学验证，并通过 C1q 阻断治疗慢性实验性自身免疫性脑脊髓炎进行治疗。 C1q 抑制是解决慢性白质炎症的潜在治疗途径，可以使用先进的 MRI 方法通过对其动态生物标志物顺磁边缘病变的纵向评估来监测炎症。