NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-06-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02530-x |
| _version_ | 1811333894213992448 |
|---|---|
| author | Zhaoqi Zhang Qiang Tan Peiwen Guo Suna Huang Zhengcai Jia Xin Liu Hua Feng Yujie Chen |
| author_facet | Zhaoqi Zhang Qiang Tan Peiwen Guo Suna Huang Zhengcai Jia Xin Liu Hua Feng Yujie Chen |
| author_sort | Zhaoqi Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T16:59:41Z |
| format | Article |
| id | doaj.art-8fb0b0f137fc40a7b30ef6732f35b1de |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-13T16:59:41Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-8fb0b0f137fc40a7b30ef6732f35b1de2022-12-22T02:38:43ZengBMCJournal of Neuroinflammation1742-20942022-06-0119112210.1186/s12974-022-02530-xNLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channelsZhaoqi Zhang0Qiang Tan1Peiwen Guo2Suna Huang3Zhengcai Jia4Xin Liu5Hua Feng6Yujie Chen7Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University)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.https://doi.org/10.1186/s12974-022-02530-xIntraventricular hemorrhageHydrocephalusNLRP3 inflammasomeChoroid plexusNKCC1Cerebrospinal fluid hypersecretion |
| spellingShingle | Zhaoqi Zhang Qiang Tan Peiwen Guo Suna Huang Zhengcai Jia Xin Liu Hua Feng Yujie Chen NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels Journal of Neuroinflammation Intraventricular hemorrhage Hydrocephalus NLRP3 inflammasome Choroid plexus NKCC1 Cerebrospinal fluid hypersecretion |
| title | NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels |
| title_full | NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels |
| title_fullStr | NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels |
| title_full_unstemmed | NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels |
| title_short | NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels |
| title_sort | nlrp3 inflammasome mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated nkcc1 channels |
| topic | Intraventricular hemorrhage Hydrocephalus NLRP3 inflammasome Choroid plexus NKCC1 Cerebrospinal fluid hypersecretion |
| url | https://doi.org/10.1186/s12974-022-02530-x |
| work_keys_str_mv | AT zhaoqizhang nlrp3inflammasomemediatedchoroidplexushypersecretioncontributestohydrocephalusafterintraventricularhemorrhageviaphosphorylatednkcc1channels AT qiangtan nlrp3inflammasomemediatedchoroidplexushypersecretioncontributestohydrocephalusafterintraventricularhemorrhageviaphosphorylatednkcc1channels AT peiwenguo nlrp3inflammasomemediatedchoroidplexushypersecretioncontributestohydrocephalusafterintraventricularhemorrhageviaphosphorylatednkcc1channels AT sunahuang nlrp3inflammasomemediatedchoroidplexushypersecretioncontributestohydrocephalusafterintraventricularhemorrhageviaphosphorylatednkcc1channels AT zhengcaijia nlrp3inflammasomemediatedchoroidplexushypersecretioncontributestohydrocephalusafterintraventricularhemorrhageviaphosphorylatednkcc1channels AT xinliu nlrp3inflammasomemediatedchoroidplexushypersecretioncontributestohydrocephalusafterintraventricularhemorrhageviaphosphorylatednkcc1channels AT huafeng nlrp3inflammasomemediatedchoroidplexushypersecretioncontributestohydrocephalusafterintraventricularhemorrhageviaphosphorylatednkcc1channels AT yujiechen nlrp3inflammasomemediatedchoroidplexushypersecretioncontributestohydrocephalusafterintraventricularhemorrhageviaphosphorylatednkcc1channels |