Ginsenoside Rg3 suppresses the NLRP3 inflammasome activation through inhibition of its assembly

Ginsenoside Rg3 is one of the main constituents of Panax ginseng. Compelling evidence has demonstrated that ginsenoside Rg3 is capable of inhibiting inflammation. However, the mechanism mediating its anti-inflammatory effects remain unclear. Here we show that ginsenoside Rg3 blocks IL-1 beta secretion and caspase-1 activation through inhibiting LPS priming and the NLRP3 inflammasome activation in human and mouse macrophages. Rg3 specifically inhibits activation of NLRP3 but not the NLRC4 or AIM2 inflammasomes. In addition, Rg3 has no effect on upstream regulation of NLRP3 inflammasome, such as K+ efflux, ROS production, or mitochondrial membrane potential. Mechanistically, Rg3 abrogates NEK7-NLRP3 interaction, and subsequently inhibits NLRP3-ASC interaction, ASC oligomerization, and speckle formation. More importantly, Rg3 can reduce IL-1 beta secretion induced by LPS in mice and protect mice from lethal endotoxic shock. Thus, our findings reveal an anti-inflammatory mechanism for Rg3 and suggest its potential use in NLRP3-driven diseases.