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NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular

Zhaoqi Zhang1,2,3, Qiang Tan1,2,3, Peiwen Guo1,2,3

  • 1Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.

Journal of Neuroinflammation
|June 21, 2022
PubMed

Insights

The NLRP3 inflammasome drives cerebrospinal fluid (CSF) overproduction after brain hemorrhage, leading to hydrocephalus. Inhibiting NLRP3 reduces CSF secretion and brain swelling, offering a new therapeutic target for hydrocephalus.

Area of Science:

  • Neuroscience
  • Immunology
  • Pathophysiology

Background:

  • Hydrocephalus is a severe complication of intracerebral hemorrhage with ventricular extension (ICH-IVH), causing cerebrospinal fluid (CSF) accumulation.
  • The choroid plexus epithelium is crucial for CSF secretion and the brain-immune interface.
  • The role of the NLRP3 inflammasome in ICH-IVH-induced hydrocephalus was previously unknown.

Purpose of the Study:

  • To investigate the role of the NLRP3 inflammasome in the pathogenesis of hydrocephalus following ICH-IVH.
  • To explore the potential mechanism of NLRP3 inflammasome activation in CSF hypersecretion.
  • To identify NLRP3 as a potential therapeutic target for hydrocephalus.

Main Methods:

  • Developed a rat model of hydrocephalus after ICH-IVH using autologous blood infusion.
  • Utilized wild-type and Nlrp3 knockout rats for comparative analysis.
  • Performed RNA-sequencing and proteomics on choroid plexus tissue, alongside in vitro experiments.

Main Results:

  • ICH-IVH rats exhibited ventricular dilation and CSF hypersecretion, with peak NLRP3 inflammasome component expression at 3 days post-hemorrhage.
  • Inhibition of NLRP3 (via MCC950 or knockout) reduced CSF secretion, ventricular dilation, and neurological deficits.
  • NLRP3 inhibition decreased NKCC1 phosphorylation, implicating the NLRP3/p-NKCC1 pathway and ion flux in CSF regulation.

Conclusions:

  • NLRP3 inflammasome activation promotes CSF hypersecretion in the choroid plexus epithelium post-hemorrhage.
  • The NLRP3/p-NKCC1 pathway is a key mechanism in hydrocephalus pathogenesis after ICH-IVH.
  • Targeting the NLRP3 inflammasome presents a novel therapeutic strategy for hydrocephalus.
Abstract

Keywords:
Cerebrospinal fluid hypersecretionChoroid plexusHydrocephalusIntraventricular hemorrhageNKCC1NLRP3 inflammasome

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