髓鞘
异染性白质营养不良
多发性硬化
小胶质细胞
星形胶质细胞
生物
病理
进行性多灶性白质脑病
神经胶质
脱髓鞘病
病变
神经科学
免疫学
医学
中枢神经系统
炎症
作者
Gerald Ponath,Sriram Ramanan,Mayyan Mubarak,William Housley,Seung‐Hoon Lee,F. Rezan Sahinkaya,Alexander O. Vortmeyer,Cedric S. Raine,David Pitt
出处
期刊:Brain
[Oxford University Press]
日期:2016-12-21
卷期号:140 (2): 399-413
被引量:148
摘要
Astrocytes are key players in the pathology of multiple sclerosis and can assume beneficial and detrimental roles during lesion development. The triggers and timing of the different astroglial responses in acute lesions remain unclear. Astrocytes in acute multiple sclerosis lesions have been shown previously to contain myelin debris, although its significance has not been examined. We hypothesized that myelin phagocytosis by astrocytes is an early event during lesion formation and leads to astroglial immune responses. We examined multiple sclerosis lesions and other central nervous system pathologies with prominent myelin injury, namely, progressive multifocal leukoencephalopathy, metachromatic leukodystrophy and subacute infarct. In all conditions, we found that myelin debris was present in most astrocytes at sites of acute myelin breakdown, indicating that astroglial myelin phagocytosis is an early and prominent feature. Functionally, myelin debris was taken up by astrocytes through receptor-mediated endocytosis and resulted in astroglial NF-κB activation and secretion of chemokines. These in vitro results in rats were validated in human disease where myelin-positive hypertrophic astrocytes showed increased nuclear localization of NF-κB and elevated chemokine expression compared to myelin-negative, reactive astrocytes. Thus, our data suggest that myelin uptake is an early response of astrocytes in diseases with prominent myelin injury that results in recruitment of immune cells. This first line response of astrocytes to myelin injury may exert beneficial or detrimental effects on the lesion pathology, depending on the inflammatory context. Modulating this response might be of therapeutic relevance in multiple sclerosis and other demyelinating conditions.
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