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.
Highlights
Inflammasome is a large multimolecular platform consisting of apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD; ASC), caspase-1, and innate immune sensors, including NOD-like receptor (NLR) family members and non-NLR receptors [1,2,3,4]
Our data show that nigericin-induced caspase-1 cleavage and IL-1β secretion in LPS-primed human peripheral blood mononuclear cells could be dramatically impaired by echinatin (Figure 1, G–J, and Supplemental Figure 1, B–C), and the inhibitory effect of echinatin on NLRP3 inflammasome activation in hPBMCs was about 2 times more potent than its effect in BM-derived macrophages (BMDMs) (Figure 1, D, E, H, and I)
The results showed that LPS transfection induced caspase-11–dependent caspase-1 cleavage and IL-1β secretion in Pam3CSK4-primed BMDMs, whereas pretreatment with echinatin before intracellular LPS stimulation resulted in the inhibition of noncanonical NLRP3 inflammasome activation (Figure 3, A–C)
Summary
Inflammasome is a large multimolecular platform consisting of apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD; ASC), caspase-1, and innate immune sensors, including NOD-like receptor (NLR) family members and non-NLR receptors [1,2,3,4]. The aberrant activation of NLRP3 inflammasome plays a crucial role in the pathogenesis of several human diseases, such as cryopyrin-associated autoinflammatory syndromes (CAPS), type 2 diabetes (T2D), gout, atherosclerosis, and neurodegenerative diseases [6,7,8,9,10,11,12,13]. Given the robust inflammatory potential of NLRP3 and its role in pathogenesis, targeting NLRP3 inflammasome has been proven to be an attractive pharmacological approach for treating the inflammatory diseases [5, 14]. Several small-molecule compounds targeting NLRP3 inflammasome have shown therapeutic benefits on NLRP3-driven diseases in a variety of animal models [5, 14,15,16,17,18,19,20,21,22], none have been used in clinic [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
