Journal Article

NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels

Tan, Qiang, Feng, Hua, Chen, Yujie, Zhang, Zhaoqi, Huang, Suna, Jia, Zhengcai, Guo, Peiwen, Liu, Xin

2022

Overview

Background Hydrocephalus is a severe complication of intracerebral hemorrhage with ventricular extension (ICH-IVH) and causes cerebrospinal fluid (CSF) accumulation. The choroid plexus epithelium plays an important role in CSF secretion and constitutes the blood–CSF barrier within the brain–immune system interface. Although the NLRP3 inflammasome, as a key component of the innate immune system, promotes neuroinflammation, its role in the pathogenesis of hydrocephalus after hemorrhage has not been investigated. Therefore, this study aimed to investigate the potential mechanism of NLRP3 in hydrocephalus to discover a potential marker for targeted therapy. Methods A rat model of hydrocephalus after ICH-IVH was developed through autologous blood infusion in wild-type and Nlrp3 −/− rats. By studying the features and processes of the model, we investigated the relationship between the NLRP3 inflammasome and CSF hypersecretion in the choroid plexus. Results The ICH-IVH model rats showed ventricular dilation accompanied by CSF hypersecretion for 3 days. Based on the choroid plexus RNA-seq and proteomics results, we found that an inflammatory response was activated. The NLRP3 inflammasome was investigated, and the expression levels of NLRP3 inflammasome components reached a peak at 3 days after ICH-IVH. Inhibition of NLRP3 by an MCC950 inflammasome inhibitor or Nlrp3 knockout decreased CSF secretion and ventricular dilation and attenuated neurological deficits after ICH-IVH. The mechanism underlying the neuroprotective effects of NLRP3 inhibition involved decreased phosphorylation of NKCC1, which is a major protein that regulates CSF secretion by altering Na + - and K + -coupled water transport, via MCC950 or Nlrp3 knockout. In combination with the in vitro experiments, this experiment confirmed the involvement of the NLRP3/p-NKCC1 pathway and Na + and K + flux. Conclusions This study demonstrates that NKCC1 phosphorylation in the choroid plexus epithelium promotes NLRP3 inflammasome-mediated CSF hypersecretion and that NLRP3 plays an important role in the pathogenesis of hydrocephalus after hemorrhage. These findings provide a new therapeutic strategy for treating hydrocephalus.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Biomedical and Life Sciences / Biomedicine / Cerebrospinal fluid / Cerebrospinal fluid hypersecretion / Cerebrospinal fluid pressure / Chloride transport / Choroid plexus / Complications and side effects / Epithelium / Hemorrhage / Hydrocephalus / Immune system / Immunology / Inflammasomes / Inflammation / Innate immunity / Intraventricular hemorrhage / Laboratory animals / Neurobiology / Neurological diseases / Neurology / Neuroprotection / Neurosciences / NKCC1 / NLRP3 inflammasome / Pathogenesis / Phosphorylation / Proteomics / Risk factors / Ventricle