The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.

中文翻译：

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出血后脑积水中脉络丛上皮的炎症依赖性脑脊液分泌过多。

脉络丛上皮（CPE）分泌的液体（脑脊液，CSF）量比其他任何上皮都要大，同时还充当血液CSF屏障，以阻止免疫细胞进入中枢神经系统。出血性脑积水（PHH）是由于脑室内出血（IVH）后脑脊液积聚导致脑室扩张的一种常见疾病，通常通过次优的脑脊液分流技术治疗。PHH经典地归因于脑脊液重吸收的主要障碍，但很少有实验证据支持该概念。相比之下，脑脊液分泌对PHH的潜在贡献却很少受到关注。在PHH的大鼠模型中，我们证明IVH在CPE中引起Toll样受体4（TLR4）和NF-κB依赖性炎症反应，与布美他尼敏感的CSF分泌增加约3倍有关。IVH诱导的CSF过度分泌是由Ste20型应激激酶SPAK的TLR4依赖性激活介导的，该激活结合，磷酸化并刺激CPE顶膜处的NKCC1共转运蛋白。TLR4或SPAK的遗传耗竭可正常化CSF分泌过多，并减轻PHH症状，对抗TLR4-NF-κB信号转导药物或SPAK-NKCC1共转运蛋白复合物的治疗也可减轻CPH症状。这些数据揭示了CSF过度分泌对PHH发病机理的前所未有的贡献，证明了TLR在调节大脑内部环境中的新作用，