Department of Anatomy II, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
Department of Anatomy, 39071 Rostock University Medical Center, Rostock, Germany.
Cells. 2019 Jan 28;8(2):94. doi: 10.3390/cells8020094.
Positron emission tomography (PET) ligands targeting the translocator protein (TSPO) represent promising tools to visualize neuroinflammation in multiple sclerosis (MS). Although it is known that TSPO is expressed in the outer mitochondria membrane, its cellular localization in the central nervous system under physiological and pathological conditions is not entirely clear. The purpose of this study was to assess the feasibility of utilizing PET imaging with the TSPO tracer, [18F]-GE180, to detect histopathological changes during experimental demyelination, and to determine which cell types express TSPO. C57BL/6 mice were fed with cuprizone for up to 5 weeks to induce demyelination. Groups of mice were investigated by [18F]-GE180 PET imaging at week 5. Recruitment of peripheral immune cells was triggered by combining cuprizone intoxication with MOG immunization (i.e., Cup/EAE). Immunofluorescence double-labelling and transgene mice were used to determine which cell types express TSPO. [18F]-GE180-PET reliably detected the cuprizone-induced pathology in various white and grey matter regions, including the corpus callosum, cortex, hippocampus, thalamus and caudoputamen. Cuprizone-induced demyelination was paralleled by an increase in TSPO expression, glia activation and axonal injury. Most of the microglia and around one-third of the astrocytes expressed TSPO. TSPO expression induction was more severe in the white matter corpus callosum compared to the grey matter cortex. Although mitochondria accumulate at sites of focal axonal injury, these mitochondria do not express TSPO. In Cup/EAE mice, both microglia and recruited monocytes contribute to the TSPO expressing cell populations. These findings support the notion that TSPO is a valuable marker for the in vivo visualization and quantification of neuropathological changes in the MS brain. The pathological substrate of an increase in TSPO-ligand binding might be diverse including microglia activation, peripheral monocyte recruitment, or astrocytosis, but not axonal injury.
正电子发射断层扫描（PET）配体靶向转位蛋白（TSPO）代表了可视化多发性硬化症（MS）神经炎症的有前途的工具。尽管已知 TSPO 在外膜表达，但在生理和病理条件下其在中枢神经系统中的细胞定位尚不完全清楚。本研究的目的是评估利用 TSPO 示踪剂[18F]-GE180 PET 成像检测实验性脱髓鞘过程中的组织病理学变化的可行性，并确定表达 TSPO 的细胞类型。C57BL/6 小鼠用杯状蛋白喂养长达 5 周以诱导脱髓鞘。在第 5 周时，通过[18F]-GE180 PET 成像对各组小鼠进行研究。将杯状蛋白中毒与 MOG 免疫相结合（即 Cup/EAE）来触发外周免疫细胞的募集。使用免疫荧光双重标记和转基因小鼠来确定哪些细胞类型表达 TSPO。[18F]-GE180-PET 可靠地检测到各种白质和灰质区域的杯状蛋白诱导的病理学，包括胼胝体、皮层、海马、丘脑和尾壳核。杯状蛋白诱导的脱髓鞘与 TSPO 表达增加、胶质细胞激活和轴突损伤相平行。大多数小胶质细胞和大约三分之一的星形胶质细胞表达 TSPO。与灰质皮层相比，白质胼胝体中的 TSPO 表达诱导更为严重。尽管线粒体聚集在局灶性轴突损伤部位，但这些线粒体不表达 TSPO。在 Cup/EAE 小鼠中，小胶质细胞和募集的单核细胞都有助于表达 TSPO 的细胞群。这些发现支持 TSPO 是 MS 大脑神经病理学变化的体内可视化和定量的有价值标志物的观点。TSPO 配体结合增加的病理基础可能是多种多样的，包括小胶质细胞激活、外周单核细胞募集或星形胶质细胞增生，但不是轴突损伤。
