Evaluation of the Choroid Plexus Epithelium Inflammation TLR4/NF-κB/NKCC1 Signal Pathway Activation in the Development of Hydrocephalus

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-10-25 DOI:10.1111/cns.70085

Hao Xu, Jiawei He, Hua Du, Xiaolei Jing, Xinfeng Liu

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Abstract

Background

Hydrocephalus is characterized by secretion, circulation, and absorption disorder of cerebrospinal fluid (CSF) with high morbidity and complication rate. The relationship between inflammation and abnormal secretion of CSF by choroid plexus epithelium (CPE) had received more attention. In this study, we aim to detect the role of Toll-like receptor 4/nuclear factor-kappa B/Na+/K+/2Cl-cotransporter 1(TLR4/NF-κB/NKCC1) signal pathway in the development of hydrocephalus.

Method

Hydrocephalus was induced in adult rats (8 weeks) by intracisternal kaolin injection, then pyrrolidinedithiocarbamate (PDTC) and bumetanide were administrated to the rats mode. Then the rat model was evaluated, and ventricular volume was calculated at different time points. Then CPE, cortex, preventricular tissue, and CSF were obtained. Protein expressions of TLR-4, NKCC/serine–threonine STE20/SPS1-related, proline-alanine-rich kinase (SPAK), pNKCC1, pSPAK, GFAP, AQP1, and AQP4 were measured by RT-PCR, western blot, and immunofluorescence (IF) stains in CPE, respectively.

Result

Our data showed that inflammation factors tumor necrosis factor-(TNF-α), interleukin 18(IL-18), and glial fibrillary acidic protein (GFAP) concentrations were significantly higher in the model group than in controls. The TLR4/NF-κB/NKCC1 signal pathway were actived by NF-κB-p65, NKCC1, pNKCC1- pSPAK complex, and Aquaporin1 (AQP1) high expression. PDTC and bumetanide use can help regular TLR4/NF-κB/NKCC1 expression and reduced AQP1 expression by down-regulate NF-B-p65 and inhibiting NKCC1, respectively. As a result, the treatment groups alleviated CPE abnormal secretion and ventricle enlargement.

Conclusion

These results confirmed that the inflammatory reaction contributes TLR4/NF-κB/NKCC1 mediated CPE abnormal secretion and consequent hydrocephalus. Regulation of TLR4/NF-κB/NKCC1 and AQP1 can prevent this process. Our study provides a strong rationale for further exploring alleviating CPE abnormal secretion as a therapeutic perspective of hydrocephalus.

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评估脉络丛上皮炎症 TLR4/NF-κB/NKCC1 信号通路在脑积水发病过程中的激活作用

背景：脑积水以脑脊液（CSF）分泌、循环和吸收障碍为特征，发病率和并发症发生率较高。炎症与脉络丛上皮（CPE）异常分泌 CSF 之间的关系受到更多关注。本研究旨在检测 Toll 样受体 4/ 核因子-kappa B/Na+/K+/2Cl 共转运体 1（TLR4/NF-κB/NKCC1）信号通路在脑积水发病中的作用：方法：通过胸腔内注射高岭土诱导成年大鼠（8周）脑积水，然后给大鼠注射吡咯烷二硫代氨基甲酸盐（PDTC）和布美他尼。然后对大鼠模型进行评估，计算不同时间点的心室容积。然后获取CPE、皮质、前室组织和CSF。通过RT-PCR、Western blot和免疫荧光（IF）染色分别检测了TLR-4、NKCC/丝氨酸-苏氨酸STE20/SPS1相关、富含脯氨酸-丙氨酸激酶（SPAK）、pNKCC1、pSPAK、GFAP、AQP1和AQP4在CPE中的蛋白表达：结果：数据显示，模型组肿瘤坏死因子（TNF-α）、白细胞介素18（IL-18）和神经胶质纤维酸性蛋白（GFAP）的浓度明显高于对照组。TLR4/NF-κB/NKCC1信号通路由NF-κB-p65、NKCC1、pNKCC1- pSPAK复合物和Aquaporin1（AQP1）的高表达激活。使用 PDTC 和布美他尼可分别通过下调 NF-B-p65 和抑制 NKCC1 来帮助规范 TLR4/NF-κB/NKCC1 的表达和减少 AQP1 的表达。因此，治疗组缓解了 CPE 的异常分泌和心室扩大：这些结果证实，炎症反应是 TLR4/NF-κB/NKCC1 介导的 CPE 异常分泌和脑积水的原因之一。调节 TLR4/NF-κB/NKCC1 和 AQP1 可以阻止这一过程。我们的研究为进一步探索将缓解 CPE 异常分泌作为脑积水的治疗角度提供了有力的依据。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.