Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus
Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus
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DOI：
10.1038/nm.4361
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发表时间：
2017-08-01
期刊：
影响因子：
82.9
通讯作者：
Kahle, Kristopher T.
中科院分区：
文献类型：
--
作者：
Karimy, Jason K.;Zhang, Jinwei;Kahle, Kristopher T.
脉络丛上皮（CPE）分泌的液体（脑脊液，CSF）量比任何其他上皮都多，同时作为血 - 脑脊液屏障，控制免疫细胞进入中枢神经系统(1)。出血后脑积水（PHH）是脑室内出血（IVH）后由于脑脊液积聚导致的脑室扩张，是一种常见疾病，通常采用不太理想的脑脊液分流技术进行治疗(2)。PHH通常被归因于脑脊液重吸收的原发性损伤，但很少有实验证据支持这一概念。相比之下，脑脊液分泌对PHH的潜在影响却很少受到关注。在PHH大鼠模型中，我们证明IVH会在CPE中引起Toll样受体4（TLR4）和NF - κB依赖的炎症反应，这与布美他尼敏感的脑脊液分泌增加约3倍有关。IVH诱导的脑脊液高分泌是由Ste20型应激激酶SPAK的TLR4依赖性激活介导的，SPAK在CPE顶膜结合、磷酸化并刺激NKCC1协同转运蛋白。TLR4或SPAK的基因缺失使过度活跃的脑脊液分泌率正常化，并减轻PHH症状，拮抗TLR4 - NF - κB信号或SPAK - NKCC1协同转运蛋白复合物的药物治疗也有同样效果。这些数据揭示了脑脊液高分泌对PHH发病机制以前未被认识到的作用，证明了Toll样受体在调节脑内环境中的新作用，并确定了一种受激酶调节的脑脊液分泌机制，可通过重新利用美国食品药品监督管理局（FDA）批准的药物来治疗脑积水。
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(1). 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(2). 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-kappa B-dependent inflammatory response in the CPE that is associated with a similar to 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-kappa B 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.