Journal
CELL PROLIFERATION
Volume 51, Issue 6, Pages -Publisher
WILEY
DOI: 10.1111/cpr.12487
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Funding
- National Natural Science Foundation of China [81601715, 31370753, 81401622]
- Basic Science and Frontier Technology Research Foundation of Chongqing science & technology commission [cstc2015jcy jBX0070]
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Objectives The non-canonical inflammasome pathway was described which engages caspase-11 to mediate pyroptosis and the subsequent release of IL-1 alpha, IL-1 beta 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. Methods 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. Results 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. Conclusion 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.
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