IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

Abstract

Background Interleukin-1 receptor-associated kinase 4 (IRAK4) plays an important role in immune modulation in various central nervous system disorders. Previous studies have found that the IRAK4 pathway is involved in lead-induced cell pyroptosis. However, there is no report on the role of IRAK4 in epilepsy models and its involvement in regulating cell pyroptosis in epilepsy, both in animal and clinical studies. Method Firstly, we performed transcriptome sequencing, qPCR, and Western blot analysis on hippocampal tissues of refractory epilepsy patients to detect the mRNA and protein levels of IRAK4 and pyroptosis-related proteins. Secondly, we successfully established a Pentylenetetrazol (PTZ)-induced seizure mouse model. We conducted behavioral tests, electroencephalography (EEG), virus injection, and molecular biology experiments to investigate the role of IRAK4 in seizure activity regulation. Results IRAK4 is upregulated in the hippocampal lesions of epilepsy patients and in the hippocampus of PTZ-induced seizure mice. In PTZ mice, IRAK4 expression is observed in neurons. Knocking out IRAK4 in PTZ mice downregulates pyroptosis-related proteins and alleviates seizure activity. Conversely, overexpressing IRAK4 in naïve mice upregulates pyroptosis-related proteins and increases PTZ-induced neuronal abnormal discharges. PDTC can reverse the increased expression of pyroptosis-related proteins caused by PTZ. PF-06650833 can alleviate seizure activity and inhibit pyroptosis in PTZ-induced seizure mice. Conclusion In summary, we hypothesize that IRAK4 promotes the expression of pyroptosis-related proteins through the NF-κB/NLRP3 pathway, suggesting that IRAK4 may promote seizure activity by mediating pyroptosis. IRAK4 plays a crucial role in epilepsy and may serve as a potential therapeutic target for this neurological disorder.