Vincenti James E, Murphy Lita, Grabert Kathleen, McColl Barry W, Cancellotti Enrico, Freeman Tom C, Manson Jean C
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom
J Virol. 2015 Dec 30;90(6):3003-17. doi: 10.1128/JVI.02613-15.
Inflammation has been proposed as a major component of neurodegenerative diseases, although the precise role it plays has yet to be defined. We examined the role of key contributors to this inflammatory process, microglia, the major resident immune cell population of the brain, in a prion disease model of chronic neurodegeneration. Initially, we performed an extensive reanalysis of a large study of prion disease, where the transcriptome of mouse brains had been monitored throughout the time course of disease. Our analysis has provided a detailed classification of the disease-associated genes based on cell type of origin and gene function. This revealed that the genes upregulated during disease, regardless of the strain of mouse or prion protein, are expressed predominantly by activated microglia. In order to study the microglia contribution more specifically, we established a mouse model of prion disease in which the 79A murine prion strain was introduced by an intraperitoneal route into BALB/cJ(Fms-EGFP/-) mice, which express enhanced green fluorescent protein under the control of the c-fms operon. Samples were taken at time points during disease progression, and histological analysis of the brain and transcriptional analysis of isolated microglia was carried out. The analysis of isolated microglia revealed a disease-specific, highly proinflammatory signature in addition to an upregulation of genes associated with metabolism and respiratory stress. This study strongly supports the growing recognition of the importance of microglia within the prion disease process and identifies the nature of the response through gene expression analysis of isolated microglia.
Inflammation has been proposed as a major component of neurodegenerative diseases. We have examined the role of key contributors to this inflammatory process, microglia, the major resident immune cell population of the brain, in a murine prion disease model of chronic neurodegeneration. Our study demonstrates that genes upregulated throughout the disease process are expressed predominantly by microglia. A disease-specific, highly proinflammatory signature was observed in addition to an upregulation of genes associated with metabolism and respiratory stress. This study strongly supports the growing recognition of the important contribution of microglia to a chronic neurodegenerative disease process.
炎症已被认为是神经退行性疾病的主要组成部分，尽管其确切作用尚未明确。我们在慢性神经退行性变的朊病毒病模型中，研究了这一炎症过程的关键促成因素——小胶质细胞（大脑中主要的常驻免疫细胞群体）所起的作用。最初，我们对一项关于朊病毒病的大型研究进行了广泛的重新分析，该研究在疾病的整个时间进程中监测了小鼠大脑的转录组。我们的分析基于基因的起源细胞类型和基因功能，对疾病相关基因进行了详细分类。这表明，在疾病期间上调的基因，无论小鼠品系或朊病毒蛋白如何，主要由活化的小胶质细胞表达。为了更具体地研究小胶质细胞的作用，我们建立了一种朊病毒病小鼠模型，通过腹腔注射途径将79A小鼠朊病毒株引入BALB/cJ(Fms-EGFP/-)小鼠，该小鼠在c-fms操纵子的控制下表达增强型绿色荧光蛋白。在疾病进展的各个时间点采集样本，并对大脑进行组织学分析以及对分离出的小胶质细胞进行转录分析。对分离出的小胶质细胞的分析显示，除了与代谢和呼吸应激相关的基因上调外，还存在疾病特异性的、高度促炎的特征。这项研究有力地支持了人们越来越认识到小胶质细胞在朊病毒病过程中的重要性，并通过对分离出的小胶质细胞进行基因表达分析确定了其反应的性质。
炎症已被认为是神经退行性疾病的主要组成部分。我们在慢性神经退行性变的小鼠朊病毒病模型中，研究了这一炎症过程的关键促成因素——小胶质细胞（大脑中主要的常驻免疫细胞群体）所起的作用。我们的研究表明，在整个疾病过程中上调的基因主要由小胶质细胞表达。除了与代谢和呼吸应激相关的基因上调外，还观察到疾病特异性的、高度促炎的特征。这项研究有力地支持了人们越来越认识到小胶质细胞对慢性神经退行性疾病过程的重要贡献。
