Roles of the pyroptosis signaling pathway in a sepsis-associated encephalopathy cell model

Objectives: The inhibition of Pyroptosis has a protective effect in sepsis-associated encephalopathy (SAE). However, the mechanisms underlying Pyroptosis in SAE remain to be elucidated.

Methods: Here, we investigated the effects of the Caspase inhibitors, Belnacasan (Beln) and Wedelolactone (Wede), on an induced model of SAE in P12 cells, using immunofluorescence, ELISA, western blotting, and flow cytometry.

Results: The cell viability decreased, IL-1β and IL-18 secretion increased, and the levels of the Caspase cleavage products, N-terminal gasdermin D, cleaved Caspase-1, and cleaved caspase-11, increased in P12 cells following combined treatment with lipopolysaccharides (LPS) and adenosine triphosphate (ATP). However, treatment with Beln or Wede ameliorated the effects induced by LPS and ATP. Neither Beln nor Wede notably affected the levels of cell apoptosis-associated proteins but these inhibitors regulated the levels of cell pyroptosis-associated proteins. Further, the combination of Beln and Wede exerted greater inhibitory effects on cell Pyroptosis than either Beln or Wede alone.

Conclusions: The results demonstrated that both the canonical and non-canonical signaling pathways of cell Pyroptosis are involved in LPS-induced cell damage and that the non-canonical signaling pathway may be involved to a greater extent. This suggests that the inhibition of Pyroptosis may exert potential therapeutic effects on SAE.