The choroid plexus (CP) is a key regulator of the central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple sclerosis (MS), but the underlying mechanisms remain largely elusive. To get a comprehensive view on the role of the CP in MS, we studied transcriptomic alterations of the human CP in progressive MS and non-neurological disease controls using RNA sequencing. We identified 17 genes with significantly higher expression in progressive MS patients relative to that in controls. Among them is the newly described long non-coding RNA HIF1A-AS3. Next to that, we uncovered disease-affected pathways related to hypoxia, secretion and neuroprotection, while only subtle immunological and no barrier alterations were observed. In an ex vivo CP explant model, a subset of the upregulated genes responded in a similar way to hypoxic conditions. Our results suggest a deregulation of the Hypoxia-Inducible Factor (HIF)-1 pathway in progressive MS CP. Importantly, cerebrospinal fluid levels of the hypoxia-responsive secreted peptide PAI-1 were higher in MS patients with high disability relative to those with low disability. These findings provide for the first time a complete overview of the CP transcriptome in health and disease, and suggest that the CP environment becomes hypoxic in progressive MS patients, highlighting the altered secretory and neuroprotective properties of the CP under neuropathological conditions. Together, these findings provide novel insights to target the CP and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.

中文翻译：

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进行性多发性硬化症中脉络丛神经的分泌和神经保护功能改变。

脉络丛（CP）通过其分泌，免疫和屏障特性，是中枢神经系统（CNS）稳态的关键调节器。越来越多的证据表明，CP在多发性硬化症（MS）的发病机理中起着关键作用，但其潜在机制仍然难以捉摸。为了全面了解CP在MS中的作用，我们使用RNA测序研究了人类CP在进行性MS和非神经疾病控制中的转录组学变化。我们确定了17个基因，在进展期MS患者中相对于对照组具有明显更高的表达。其中之一是新近描述的长非编码RNA HIF1A-AS3。接下来，我们发现了与缺氧，分泌和神经保护有关的疾病影响途径，而仅观察到细微的免疫学变化和无屏障改变。在离体CP外植体模型中，上调基因的一个子集对缺氧条件的反应相似。我们的研究结果表明进展性MS CP中的缺氧诱导因子（HIF）-1通路的放松。重要的是，与低残疾患者相比，高残疾MS患者的低氧反应性分泌肽PAI-1的脑脊液水平更高。这些发现首次提供了健康和疾病中CP转录组的完整概述，并表明进行性MS患者的CP环境变得缺氧，突出了在神经病理条件下CP的分泌和神经保护特性发生了改变。一起，