The pannexin-1 channel regulates pyroptosis through autophagy in a mouse model of sepsis-associated encephalopathy
Yupeng Lei, Ruixi Zhou, Xuemei Sun, Fajuan Tang, Hu Gao, Lin Chen, Xihong Li
Abstract
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis. Pyroptosis and autophagy are important mechanisms in the pathogenesis of sepsis, and also pannexin-1 is involved in the occurrence of sepsis. However, role of pannexin-1 in SAE and its relationship with pyroptosis and autophagy are unclear. This study examined the relationship between pannexin-1 and pyroptosis, and further explore the relationship between pyroptosis and autophagy in SAE mice. METHODS: A SAE mouse model was established by cecal ligation and puncture (CLP). Different groups of mice were administrated probenecid (PRB), 3-methyladenine (3-MA), or a vehicle control and the survival rates were monitored at different time points. Cortical pathological changes were examined by hematoxylin and eosin (HE) staining. The expression of cortical pannexin-1 and adenosine monophosphate-activated protein kinase (AMPK), as well as pyroptosis and autophagy related proteins, was detected by Western blotting and immunofluorescence analysis. The ultrastructure of neurons was observed by transmission electron microscopy. RESULTS: Septic mice showed significantly higher rates of mortality and cortical pathological change compared to control mice. In addition, the pannexin-1 and AMPK signaling pathway were activated in the cerebral cortex of the septic mice, coupled with the activation of pyroptosis and incomplete activation of autophagy. Inhibition of pannexin-1 expression reduce the rates of mortality and the cortical pathological changes in the mice, further activated the AMPK signaling pathway, inhibited pyroptosis, and completely activated autophagy. The inhibition of autophagy may cause pyroptosis to reactivate. CONCLUSIONS: The present findings suggested that in SAE mice, pannexin-1 may regulate neuronal pyroptosis through autophagy. Moreover, the regulation of autophagy may be related to the AMPK signaling pathway. Inhibiting pannexin-1 expression in SAE mice may have a neuroprotective effect.