Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis

小胶质细胞 神经退行性变 多发性硬化 神经炎症 白质 生物 神经胶质 病理 巨噬细胞 免疫学 神经科学 医学 炎症 中枢神经系统 疾病 体外 生物化学 磁共振成像 放射科
作者
Tobias Zrzavy,Simon Hametner,Isabella Wimmer,Oleg Butovsky,Howard L. Weiner,Hans Lassmann
出处
期刊:Brain [Oxford University Press]
卷期号:140 (7): 1900-1913 被引量:533
标识
DOI:10.1093/brain/awx113
摘要

Microglia and macrophages accumulate at the sites of active demyelination and neurodegeneration in the multiple sclerosis brain and are thought to play a central role in the disease process. We used recently described markers to characterize the origin and functional states of microglia/macrophages in acute, relapsing and progressive multiple sclerosis. We found microglia activation in normal white matter of controls and that the degree of activation increased with age. This microglia activation was more pronounced in the normal-appearing white matter of patients in comparison to controls and increased with disease duration. In contrast to controls, the normal-appearing white matter of patients with multiple sclerosis showed a significant reduction of P2RY12, a marker expressed in homeostatic microglia in rodents, which was completely lost in active and slowly expanding lesions. Early stages of demyelination and neurodegeneration in active lesions contained microglia with a pro-inflammatory phenotype, which expressed molecules involved in phagocytosis, oxidative injury, antigen presentation and T cell co-stimulation. In later stages, the microglia and macrophages in active lesions changed to a phenotype that was intermediate between pro- and anti-inflammatory activation. In inactive lesions, the density of microglia/macrophages was significantly reduced and microglia in part converted to a P2RY12+ phenotype. Analysis of TMEM119, which is expressed on microglia but not on recruited macrophages, demonstrated that on average 45% of the macrophage-like cells in active lesions were derived from the resident microglia pool. Our study demonstrates the loss of the homeostatic microglial signature in active multiple sclerosis with restoration associated with disease inactivity.
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