Role of Stat3 in NLRP3/caspase‐1‐mediated hippocampal neuronal pyroptosis in epileptic mice

Abstract

Epilepsy, a fairly common neurological disorder, is linked to various sequelae and greatly impairs the quality of life. Meanwhile, there is evidence to suggest an association between pyroptosis and epilepsy. Accordingly, the current study sought to determine the role of signal transduction activator of transcription 3 (Stat3) in pyroptosis in epileptic mice. First, epileptic mouse models were induced by lithium chloride, atropine, and pilocarpine, and HT22 cells were treated with lipopolysaccharide (LPS) to establish in vitro hippocampal neuronal inflammation models. Subsequently, Stat3, NOD‐like receptor protein 3 (NLRP3), cleaved‐caspase‐1, gasdermin D (GSDMD)‐N, activated Stat3 (p‐Stat3), and H3K9Ac levels were detected in the mouse hippocampus and HT22 cells. Morris water maze test was further performed to detect changes in the learning and memory abilities of epileptic mice, and hematoxylin‐eosin staining and Nissl staining were conducted to detect the pathological injury. HT22 cell proliferation and apoptosis were also detected using a cell counting kit‐8 assay and flow cytometry. An enzyme‐linked immunosorbent assay was adopted to detect Interleukin (IL)‐1β and IL‐18 concentrations in the mouse hippocampus and HT22 cells. Furthermore, the enrichment of H3K9Ac and p‐Stat3 in the NLRP3 promoter region was detected with the help of a chromatin immunoprecipitation assay. The obtained findings revealed that Stat3 was highly expressed in the hippocampus of epileptic mice and LPS‐treated HT22 cells. Meanwhile, Stat3 silencing brought about improvements in the learning and memory abilities of the mice, in addition to alleviation of hippocampal neuronal damage and pyroptosis‐related factors in hippocampal tissue and HT22 cells. We also observed that Stat3 bound to the NLRP3 promoter to promote H3K9 acetylation and NLRP3 transcription. Moreover, increasing H3K9Ac in cells annulled the inhibition of silencing Stat3 on neuronal pyroptosis. To conclude, our findings revealed that Stat3 bound to the NLRP3 promoter to augment H3K9 acetylation, NLRP3 transcription, and NLRP3/caspase‐1‐mediated neuronal pyroptosis, resulting in aggravation of neuronal damage in epileptic mice.

GPR120 modulates epileptic seizure and neuroinflammation mediated by NLRP3 inflammasome

“…Hua et al also found that activation of NLRP3 and caspase-1 in neurons can also lead to neuroinflammation [40]. NLRP3 has been found to be significantly elevated in neurons [41] and microglia [42] in the epileptic brain, which is mainly stimulated by intracellular environment and cell membrane receptor signals [43]. Moreover, GPR120 is a membrane receptor that can be internalized into cells to regulate inflammatory factors under disease conditions [44].…”

The GLCCI1/STAT3 pathway: A novel pathway involved in diabetic cognitive dysfunction and the therapeutic effect of salidroside

“…Additionally, Ting-Fa Zhou's research indicated that the JAK2/STAT3 signalling pathway is involved in the protective effect of recombinant human erythropoietin against neuronal alterations and cognitive de cits in experimental endotoxaemia [24] . Furthermore, Qian Jiang's study implicated Stat3-induced activation of NLRP3/Caspase-1-mediated neuronal pyroptosis in epilepsy development in mice [25] .…”

Suppression of NLRP3 Inflammasome by Dihydroarteannuin via the HIF‐1α and JAK3/STAT3 Signaling Pathway Contributes to Attenuation of Collagen-Induced Arthritis in Mice

“…Previous research indicated that the phosphorylated STAT3 (p-STAT3) facilitated histone H3 and H4 acetylation on Nlrp3 promoter, which promoted the expression of NLRP3 ( Liu et al, 2018 ; Jiang et al, 2021b ). STAT3 is one of the major signal transducers of JAKs and plays a role in inducing and maintaining an inflammatory microenvironment ( Zare et al, 2015 ).…”