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–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.

Analysis of risk factors of hydrocephalus after intraventricular hemorrhage in infants

“…According to some researchers [11,12], IVH causes blood to build up in the ventricle and cistern, clots to break up, and hemoglobin, iron, thrombin, and complements to be released. These blood components may contribute to in ammation, glutamate toxicity, and oxidative stress, which can harm oligodendrocyte precursor cells and lessen myelin.…”

A year in review: brain barriers and brain fluids research in 2022

“…The choroid plexus is thought by most to be the primary site of CSF secretion with a lesser contribution from the neurovasculature. In terms of CSF secretion, there has been particular focus on the role of the sodium/potassium/chloride cotransporter, NKCC1 [ 43 – 46 ], and transient receptor potential vanilloid 4 (TRPV4) channels [ 44 , 47 ] at the choroid plexus epithelium. Such research may lead to a clinical method for reducing CSF production.…”

“…For instance, Alzheimer’s disease causes marked changes in choroid plexus myeloid cells [ 50 ]. The NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in CP hypersecretion after intraventricular hemorrhage [ 46 ]. The choroid plexus is also a target for reducing T cell infiltration in experimental autoimmune encephalitis [ 51 ] and there are very early inflammatory changes at the choroid plexus after intracerebral hemorrhage [ 52 ].…”

Discovering hematoma-stimulated circuits for secondary brain injury after intraventricular hemorrhage by spatial transcriptome analysis

“…IVH is one of the common complications after various acute brain injuries ( 1 – 3 ) that causes severe mortality and mobility dysfunction and is a great economic and societal burden. To date, the gold standard for the treatment of IVH is hematoma removal and hydrocephalus prevention ( 4 ), which relieves the general pathophysiological effects and elevated intracranial pressure in the lateral walls of the ventricles ( 3 ) as well as reduces the obstructions and inflammatory responses from blood metabolic stimulations ( 5 , 6 ). However, a recently completed large-scale randomized clinical trial (CLEAR III, Trial No.…”