Inhibiting the IRAK4/NF-κB/NLRP3 signaling pathway can reduce pyroptosis in hippocampal neurons and seizure episodes in epilepsy

Ting Zhao; Xuefei Zhang; Xiaoxiao Cui; Songxue Su; Lei Li; Yanan Chen; Na Wang; Lei Sun; Jianyuan Zhao; Jiewen Zhang; Xiong Han; Jing Cao

doi:10.1016/j.expneurol.2024.114794

Inhibiting the IRAK4/NF-κB/NLRP3 signaling pathway can reduce pyroptosis in hippocampal neurons and seizure episodes in epilepsy

Exp Neurol. 2024 Apr 27:377:114794. doi: 10.1016/j.expneurol.2024.114794. Online ahead of print.

Authors

Ting Zhao¹, Xuefei Zhang¹, Xiaoxiao Cui¹, Songxue Su¹, Lei Li¹, Yanan Chen¹, Na Wang¹, Lei Sun¹, Jianyuan Zhao², Jiewen Zhang³, Xiong Han⁴, Jing Cao⁵

Affiliations

¹ Department of Neurology and Basic Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
² Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Electronic address: zhaojy@vip.163.com.
³ Department of Neurology and Basic Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China. Electronic address: zhangjiewen@zzu.edu.cn.
⁴ Department of Neurology and Basic Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China. Electronic address: hanxiong@zzu.edu.cn.
⁵ Department of Neurology and Basic Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China. Electronic address: caojing@zzu.edu.cn.

PMID: 38685307
DOI: 10.1016/j.expneurol.2024.114794

Abstract

Background: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays an important role in immune modulation in various central nervous system disorders. However, IRAK4 has not been reported in epilepsy models in animal and clinical studies, nor has its involvement in regulating pyroptosis in epilepsy.

Method: First, we performed transcriptome sequencing, quantitative real-time polymerase chain reaction, and western blot analysis on the hippocampal tissues of refractory epilepsy patients to measure the mRNA and protein levels of IRAK4 and pyroptosis-related proteins. Second, we successfully established a pentylenetetrazol (PTZ)-induced seizure mouse model. We conducted behavioral tests, electroencephalography, virus injection, and molecular biology experiments to investigate the role of IRAK4 in seizure activity regulation.

Results: IRAK4 is upregulated in the hippocampus of epilepsy patients and PTZ-induced seizure model mice. IRAK4 expression is observed in the hilar neurons of PTZ-induced mice. Knocking down IRAK4 in PTZ-induced mice downregulated pyroptosis-related protein expression and alleviated seizure activity. Overexpressing IRAK4 in naive mice upregulated pyroptosis-related protein expression and increased PTZ-induced abnormal neuronal discharges. IRAK4 and NF-κB were found to bind to each other in patient hippocampal tissue samples. Pyrrolidine dithiocarbamate reversed the pyroptosis-related protein expression increase caused by PTZ. PF-06650833 alleviated seizure activity and inhibited pyroptosis in PTZ-induced seizure mice.

Conclusion: IRAK4 plays a key role in the pathological process of epilepsy, and its potential mechanism may be related to pyroptosis mediated by the NF-κB/NLRP3 signaling pathway. PF-06650833 has potential as a therapeutic agent for alleviating epilepsy.

Keywords: Epilepsy; IRAK4; NF-κB; NLRP3 inflammasome; Pyroptosis.