Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC
Jia Zhao, Hongbin Liu, Zhixian Hong, Wei Luo, Wenqing Mu, Xiaorong Hou, Guang Xu, Guang Xu, Lutong Ren, Tingting Liu, Jincai Wen, Wei Shi, Ziying Wei, Yongping Yang, Wenjun Zou, Jun Zhao, Xiaohe Xiao, Zhaofang Bai, Xiaoyan Zhan, Zhaofang Bai, Xiaoyan Zhan
Abstract
BACKGROUND: Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study. METHODS: IL-1β and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1β levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry. RESULTS: Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH. CONCLUSIONS: Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases.