Echinatin effectively protects against NLRP3 inflammasome–driven diseases by targeting HSP90
Guang Xu, Shubin Fu, Xiaoyan Zhan, Zhilei Wang, Ping Zhang, Wei Shi, Nan Qin, Yuanyuan Chen, Chunyu Wang, Ming Niu, Yuming Guo, Jiabo Wang, Zhaofang Bai, Xiaohe Xiao
Guang Xu, Shubin Fu, Xiaoyan Zhan, Zhilei Wang, Ping Zhang, Wei Shi, Nan Qin, Yuanyuan Chen, Chunyu Wang, Ming Niu, Yuming Guo, Jiabo Wang, Zhaofang Bai, Xiaohe Xiao
View: Text | PDF
Research Article Immunology Inflammation

Echinatin effectively protects against NLRP3 inflammasome–driven diseases by targeting HSP90

Abstract

Aberrant activation of NLRP3 inflammasome has been implicated in a variety of human inflammatory diseases, but currently, no pharmacological NLRP3 inhibitor has been approved. In this study, we showed that echinatin, the ingredient of the traditional herbal medicine licorice, effectively suppresses the activation of NLRP3 inflammasome in vitro and in vivo. Further investigation revealed that echinatin exerts its inhibitory effect on NLRP3 inflammasome by binding to heat-shock protein 90 (HSP90), inhibiting its ATPase activity and disrupting the association between the cochaperone SGT1 and HSP90-NLRP3. Importantly, in vivo experiments demonstrated that administration of echinatin obviously inhibits NLRP3 inflammasome activation and ameliorates LPS-induced septic shock and dextran sodium sulfate–induced (DSS-induced) colitis in mice. Moreover, echinatin exerted favorable pharmacological effects on liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis (NASH). Collectively, our study identifies echinatin as a potentially novel inhibitor of NLRP3 inflammasome, and its use may be developed as a therapeutic approach for the treatment of NLRP3-driven diseases.

Authors

Guang Xu, Shubin Fu, Xiaoyan Zhan, Zhilei Wang, Ping Zhang, Wei Shi, Nan Qin, Yuanyuan Chen, Chunyu Wang, Ming Niu, Yuming Guo, Jiabo Wang, Zhaofang Bai, Xiaohe Xiao

×

Figure 4

Echinatin binds to HSP90 and inhibits its ATPase activity.

Options: View larger image (or click on image) Download as PowerPoint
Echinatin binds to HSP90 and inhibits its ATPase activity. (A) Cell lysa...
(A) Cell lysates of LPS-primed BMDMs incubated with echinatin-sepharose and different concentrations of free echinatin (0.4 mM and 0.8 mM). The pull-down samples and input were analyzed by IB. (B) Effect of echinatin on the ATPase activity of HSP90β. After incubation HSP90β plus indicated different concentrations of free echinatin (0.25 mM, 0.5 mM, and 1 mM) and geldanamycin (GA, 20 μM), ATP was measured by CellTiter-Glo and normalized to the control. (C) Cell lysates of LPS-primed BMDMs with or without nigericin incubated with echinatin-sepharose. The pull-down samples and input were analyzed by IB. (D) 293T cells were transfected with indicated plasmids and then treated with vehicle, echinatin (80 μM), and GA (20 μM). Immunoprecipitation was performed with anti–Flag M2 agarose beads; the IB for HSP90, SGT1, and Flag is shown. (E) LPS-primed BMDMs were pretreated with vehicle, echinatin (40 μM), or GA (20 μM) and then stimulated with nigericin, Lfn-FliC, or poly(dA:dT). Cleaved caspase-1, production of IL-1β, and cross-linked ASC in the Triton X–insoluble pellet were examined by IB analysis. Data are expressed as mean ± SEM (n = 3/group, resulting from 3 independent experiments). One-way ANOVA, followed by Dunnett’s post hoc test, was used to assess the differences of multiple groups (B), **P < 0.01, ***P < 0.001 compared with control.