Cathepsin B regulates non-canonical NLRP3 inflammasome pathway by modulating activation of caspase-11 in Kupffer cells.

Abstract

The non-canonical inflammasome pathway was described which engages caspase-11 to mediate pyroptosis and the subsequent release of IL-1α, IL-1β and IL-18 in TLR4-independent way. Cathepsin B is capable of activating caspase-11 under cell-free conditions which may regulate non-canonical NLRP3 inflammasome pathway. In this study, we aimed to further investigate cathepsin B as potential activators of proinflammatory caspases which may be released upon proinflammatory stimuli and regulate non-canonical NLRP3 inflammasome pathway by modulating the activity of caspase-11. Pharmacological and gene-silencing approaches were used to evaluate the impact of cathepsin B on regulating non-canonical NLRP3 inflammasome pathway in wild-type and TLR4-/- Kupffer cells. A sepsis model was also created to investigate the effect of cathepsin B on survival. Meanwhile, cathepsin B activity and the expression level of caspase-4 were detected in human peripheral blood mononuclear cells (PBMC) which were separated from patients suffered from SIRS or sepsis and healthy volunteers. LPS stimulation caused cathepsin B activity and caspase-11 expression increase in TLR4-/- mice. Cathepsin B activity inhibition reduced the activation of caspase-11 and inflammasome and benefited survival in TLR4-/- mice. Upregulation of cathepsin B activity and caspase-4 activation was found in PBMC of patients with SIRS or sepsis. Our results suggest a critical role for cathepsin B as activators of proinflammatory caspases-11 and the regulatory effect in LPS-induced caspases-11-dependent necrosis.