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NLRP3 Inflammasome Activation Contributes to Seizure Susceptibility in Anti-NMDAR Encephalitis: Evidence from
Hanyu Luo1, Jiaxin Yang1, Yuhang Li1
1Department of Neurology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Abstract:
Seizures are common in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, yet the mechanisms beyond antibody-mediated NMDAR hypofunction remain poorly understood. This study investigated whether microglial NLRP3 inflammasome activation increases seizure susceptibility and whether its inhibition confers protection. In a pediatric cohort of sixty patients, serum levels of NLRP3 and IL-1β were elevated in patients compared with controls. Multivariable models indicated that NLRP3 was independently associated with seizure presence, whereas IL-1β did not retain independent significance when modeled alongside NLRP3, and model discrimination improved modestly when both markers were included. In an active-immunization mouse model using the GluN1356-385 peptide, pentylenetetrazol exposure resulted in shorter seizure latency and increased severity, accompanied by cortical microglial activation and upregulation of the NLRP3-ASC-caspase-1-IL-1β pathway. Pharmacologic NLRP3 inhibition with MCC950 elevated seizure threshold and reduced seizure burden. Correspondingly, cortical c-Fos/NeuN staining revealed heightened neuronal activation in immunized mice, which was attenuated by MCC950. Notably, MCC950 did not reverse the decrease in membrane NMDAR levels, indicating seizure protection independent of NMDAR function recovery. These clinical and experimental results indicate that NLRP3 inflammasome contributes to lowered seizure threshold in anti-NMDAR encephalitis, operating downstream of or in parallel to NMDAR hypofunction. NLRP3 represents a potential serum biomarker for seizure risk and a promising adjunct therapeutic target, supporting further evaluation of inflammasome inhibition during acute disease stages.
Insights
Microglial NLRP3 inflammasome activation increases seizure risk in anti-N-methyl-D-aspartate receptor encephalitis. Inhibiting NLRP3 offers protection, suggesting it as a therapeutic target for seizures.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Encephalitis Research
Background:
- Seizures are prevalent in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but mechanisms beyond NMDAR hypofunction are unclear.
- Microglial NLRP3 inflammasome activation is implicated in neurological disorders.
- Understanding NLRP3's role in anti-NMDAR encephalitis seizures is crucial for therapeutic development.
Purpose of the Study:
- To investigate if microglial NLRP3 inflammasome activation elevates seizure susceptibility in anti-NMDAR encephalitis.
- To determine if NLRP3 inflammasome inhibition provides protection against seizures.
- To explore NLRP3 as a potential biomarker for seizure risk.
Main Methods:
- Analysis of serum NLRP3 and IL-1β levels in a pediatric cohort with anti-NMDAR encephalitis.
- Utilizing an active-immunization mouse model of anti-NMDAR encephalitis.
- Administering pentylenetetrazol to induce seizures and MCC950 to inhibit NLRP3.
- Assessing seizure latency, severity, cortical microglial activation, neuronal activation (c-Fos/NeuN), and NMDAR levels.
Main Results:
- Elevated serum NLRP3 levels were independently associated with seizure presence in patients.
- NLRP3 inflammasome activation (NLRP3-ASC-caspase-1-IL-1β pathway) was observed in the mouse model.
- Pharmacologic NLRP3 inhibition with MCC950 reduced seizure burden and neuronal activation.
- MCC950 conferred seizure protection independently of NMDAR function recovery.
Conclusions:
- Microglial NLRP3 inflammasome activation contributes to increased seizure susceptibility in anti-NMDAR encephalitis.
- NLRP3 acts downstream or parallel to NMDAR hypofunction in seizure pathogenesis.
- NLRP3 is a potential serum biomarker for seizure risk and an adjunct therapeutic target in anti-NMDAR encephalitis.
