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研究揭示淋巴细胞-小胶质细胞-星型细胞轴在慢性多发性硬化症中的作用
作者:小柯机器人 发布时间:2021/9/12 12:50:53

美国国立卫生研究院Daniel S. Reich、Martina Absinta等研究人员合作发现淋巴细胞-小胶质细胞-星型细胞轴在慢性多发性硬化症中的作用。相关论文于2021年9月8日在线发表在《自然》杂志上。

研究人员表示,多发性硬化症(MS)的病变在形成后的几个月内并没有得到解决,而是存在持续的脱髓鞘和轴突变性,在体内可通过MRI扫描的顺磁性边缘识别。

为了确定这种能力丧失的、渐进的神经退行性状态的机制,并促进新的治疗药物的发展,研究人员使用MRI知情的单核RNA测序来描述处于不同炎症阶段的脱髓鞘白质病变边缘。研究人员发现了明显的胶质和免疫细胞的多样性,尤其是在慢性炎症的病变边缘。研究人员定义了"多发性硬化症中的小胶质细胞"(MIMS)和"多发性硬化症中的星形细胞",这些胶质细胞表型显示了神经退行性程序。MIMS的转录谱与其他神经退行性疾病中的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有共同的机制,可以从类似的治疗方法中受益。

研究人员确定补体成分1q(C1q)是MIMS激活的关键媒介,在MS组织中通过免疫组化验证,在实验性自身免疫性脑脊髓炎小鼠中通过小胶质细胞特异性C1q敲除进行遗传验证,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。抑制C1q是解决慢性白质炎症的一个潜在治疗途径,可以通过使用先进的MRI方法对其动态生物标志物——顺磁性边缘病变,进行纵向评估来监测。

附:英文原文

Title: A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis

Author: Absinta, Martina, Maric, Dragan, Gharagozloo, Marjan, Garton, Thomas, Smith, Matthew D., Jin, Jing, Fitzgerald, Kathryn C., Song, Anya, Liu, Poching, Lin, Jing-Ping, Wu, Tianxia, Johnson, Kory R., McGavern, Dorian B., Schafer, Dorothy P., Calabresi, Peter A., Reich, Daniel S.

Issue&Volume: 2021-09-08

Abstract: 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 scans1,2,3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4,5,6 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.

DOI: 10.1038/s41586-021-03892-7

Source: https://www.nature.com/articles/s41586-021-03892-7

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html