Department of Neurology, Focus Program Translational Neuroscience, Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Proc Natl Acad Sci U S A. 2021 Sep 7;118(36). doi: 10.1073/pnas.2025000118.
Neuroinflammation is a pathophysiological hallmark of multiple sclerosis and has a close mechanistic link to neurodegeneration. Although this link is potentially targetable, robust translatable models to reliably quantify and track neuroinflammation in both mice and humans are lacking. The choroid plexus (ChP) plays a pivotal role in regulating the trafficking of immune cells from the brain parenchyma into the cerebrospinal fluid (CSF) and has recently attracted attention as a key structure in the initiation of inflammatory brain responses. In a translational framework, we here address the integrity and multidimensional characteristics of the ChP under inflammatory conditions and question whether ChP volumes could act as an interspecies marker of neuroinflammation that closely interrelates with functional impairment. Therefore, we explore ChP characteristics in neuroinflammation in patients with multiple sclerosis and in two experimental mouse models, cuprizone diet-related demyelination and experimental autoimmune encephalomyelitis. We demonstrate that ChP enlargement-reconstructed from MRI-is highly associated with acute disease activity, both in the studied mouse models and in humans. A close dependency of ChP integrity and molecular signatures of neuroinflammation is shown in the performed transcriptomic analyses. Moreover, pharmacological modulation of the blood-CSF barrier with natalizumab prevents an increase of the ChP volume. ChP enlargement is strongly linked to emerging functional impairment as depicted in the mouse models and in multiple sclerosis patients. Our findings identify ChP characteristics as robust and translatable hallmarks of acute and ongoing neuroinflammatory activity in mice and humans that could serve as a promising interspecies marker for translational and reverse-translational approaches.
神经炎症是多发性硬化症的一种病理生理学特征，与神经退行性变有密切的机制联系。尽管这种联系可能是可靶向的，但缺乏可靠的、可转化的模型来定量和跟踪小鼠和人类的神经炎症。脉络丛（ChP）在调节免疫细胞从脑实质向脑脊液（CSF）的转运中起着关键作用，最近作为炎症性脑反应起始的关键结构引起了人们的关注。在转化框架中，我们在这里解决了炎症条件下 ChP 的完整性和多维特征，并质疑 ChP 体积是否可以作为神经炎症的种间标志物，与功能障碍密切相关。因此，我们探索了多发性硬化症患者和两种实验性小鼠模型（杯状醇饮食相关脱髓鞘和实验性自身免疫性脑脊髓炎）中的 ChP 特征。我们证明，从 MRI 重建的 ChP 增大与急性疾病活动高度相关，无论是在研究的小鼠模型还是在人类中。在进行的转录组分析中显示了 ChP 完整性和神经炎症分子特征的密切依赖性。此外，用那他珠单抗调节血脑屏障的药物治疗可防止 ChP 体积增加。ChP 增大与在小鼠模型和多发性硬化症患者中出现的新的功能障碍密切相关。我们的发现将 ChP 特征确定为在小鼠和人类中急性和持续神经炎症活动的稳健和可转化特征，可作为转化和反向转化方法的有前途的种间标志物。
