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

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

  • J Neuroinflammation. 2022 Jun 21;19(1):163. doi: 10.1186/s12974-022-02530-x.
Zhaoqi Zhang 1 2 3,  Qiang Tan 1 2 3,  Peiwen Guo 1 2 3,  Suna Huang 1 2 3,  Zhengcai Jia 1 2 3,  Xin Liu 1 2 3,  Hua Feng 4 5 6,  Yujie Chen 7 8 9 10
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 3 Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 4 Department 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. [email protected].
  • 5 Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. [email protected].
  • 6 Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. [email protected].
  • 7 Department 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. [email protected].
  • 8 Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. [email protected].
  • 9 Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. [email protected].
  • 10 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China. [email protected].
PMID: 35729645 DOI: 10.1186/s12974-022-02530-x
Abstract

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.

Keywords

Cerebrospinal fluid hypersecretion; Choroid plexus; Hydrocephalus; Intraventricular hemorrhage; NKCC1; NLRP3 inflammasome.

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