Endoplasmic reticulum stress-induced CHOP activation mediates NLRP3 inflammasome-dependent pyroptosis in...

Recent studies have unraveled a striking association between endoplasmic reticulum (ER) stress and the NLRP3 inflammasome. Prior research has documented that activation of the NLRP3 inflammasome contributes to BDE-47-induced cytotoxicity, while ER stress has also been implicated in mediating the toxic effects of brominated diphenyl ethers (BDEs). However, the intricate interplay between ER stress and the NLRP3 inflammasome, as well as their combined impact on neuronal pyroptosis and cognitive deficits following BDE-47 exposure, remains underexplored. Our results revealed pronounced ER stress in BDE-47-treated mouse hippocampi and SH-SY5Y cells, as evidenced by significantly elevated expression of key ER stress markers, including p-PERK, p-IRE1α, ATF6, and CHOP, and accompanied by observable ER dilation. Further mechanistic investigations demonstrated that BDE-47-induced upregulation of CHOP activates the NLRP3 inflammasome, thereby triggering subsequent neuronal pyroptosis in SH-SY5Y cells. Notably, intervention with either the ER stress inhibitor 4-PBA or CHOP siRNA effectively abrogated BDE-47-induced, NLRP3 inflammasome-dependent neuronal pyroptosis. Furthermore, administration of the ER stress inhibitor 4-PBA or the NLRP3 inflammasome inhibitor MCC950 substantially mitigated hippocampal neuronal injury and synaptic dysfunction, while concomitantly alleviating cognitive deficits in BDE-47-exposed mice. Collectively, integrative analysis of our experimental data illuminates previously unrecognized mechanisms underlying BDE-47-induced neurotoxicity, suggesting that targeting ER stress-mediated activation of the NLRP3 inflammasome and the ensuing neuronal pyroptosis could represent a potential therapeutic strategy for ameliorating BDE-47-associated neurobehavioral impairments.