Nan Chen1,2, Zhibing Ou1, Wenfeng Zhang1, Xiwen Zhu2, Peizhi Li1, Jianping Gong1. 1. Chongqing Key Laboratory of Hepatobiliary Surgery, Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. 2. Department of Anesthesia, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract
OBJECTIVES: 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. 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.
OBJECTIVES: 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. 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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