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
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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

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Figure 3

Echinatin does not directly target the ASC oligomerization and does not block K+ efflux or mitochondrial damage.

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Echinatin does not directly target the ASC oligomerization and does not ...
(A–C) LPS-primed BMDMs were pretreated with echinatin (40 μM) or vehicle and then stimulated with nigericin, poly(dA:dT), and Lfn-FliC — or Pam3CSK4-primed BMDMs were pretreated with echinatin (40 μM) or vehicle and then stimulated with transfected LPS. Cleaved caspase-1 and production of IL-1β were examined by IB analysis (A), and activity of caspase-1 (B) and secretion of IL-1β (C) in SN were assessed. (D) IB analysis of cross-linked ASC in the Triton X–insoluble pellet from LPS-primed BMDMs pretreated with echinatin (40 μM) or vehicle and then stimulated with nigericin, poly(dA:dT), Lfn-FliC, or Pam3CSK4-primed BMDMs were pretreated with echinatin (40 μM) or vehicle and then stimulated with transfected LPS. (E) Qualification of intracellular potassium in LPS-primed BMDMs pretreated with indicated dose of echinatin and stimulated with nigericin. (F) Staining with MitoTracker red in LPS-primed BMDMs pretreated with echinatin (40 μM) or vehicle and then stimulated with nigericin. Scale bar: 5 μm. Data are expressed as mean ± SEM (n = 3/group, resulting from 3 independent experiments). Statistics differences were analyzed by unpaired t test (B and C) or 1-way ANOVA followed by Dunnett’s post hoc test (E). **P < 0.01, ***P < 0.001.