Increased inflammasome-activated pyroptosis mediated by caspase-1 in Rasmussen's encephalitis

Rasmussen's encephalitis (RE) is a rare, progressive disease characterized by unilateral cerebral hemisphere atrophy. Studies showed that inflammatory response and overexpressed chemokines were present in RE patients. The present study aims to determine whether caspase-1- mediated neuronal pyroptosis occurred in RE.

Immunohistochemistry and Western blotting analysis were used to examine the expression of Gasdermin D (GSDMD), NOD-like receptor protein 1 (NLRP1), NOD-like receptor protein 3 (NLRP3), caspase-1, and pro-caspase-1 in RE and control cortical specimens (n = 14). Perilesional tissue specimens from six focal cortical dysplasia (FCD) cases were used as controls. Double staining showed the colocalization of GSDMD, NLRP1, NLRP3 and caspase-1. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the amount of interleukin (IL)-1β and IL-18 in RE cortical specimens.

Compared with the control cortex, we found higher GSDMD expression in the cytoplasm of neurons in RE cortex but no detectable expression in astrocytes and microglia. Further analysis revealed that NLRP1, NLRP3, caspase-1 and its precursor pro-caspase-1 were also upregulated in the RE, and predominantly localized in the cytoplasm of the neurons. In addition, significantly higher levels of IL-1β and IL-18 were present in the RE group compared with the control group.

Our results suggest that pyroptosis represents an important pathway for neuronal loss in the pathological processes associated with RE, and that targeting the canonical inflammasome pathway of pyroptosis may provide potential therapeutic value for RE.