Taraxasterol (TAS) is an active ingredient of Dandelion (Taraxacum mongolicum Hand. -Mazz.), a medicinal plant that has long been used in China for treatment of inflammatory disorders. But the underlying mechanism for its
therapeutic effects on inflammatory disorders is not completely clear.
Inflammasome activation is a critical step of innate immune response to
infection and aseptic
inflammation. Among the various types of
inflammasome sensors that has been reported, NLR family pyrin domain containing 3 (NLRP3) is implicated in various inflammatory diseases and therefore has been most extensively studied. In this study, we aimed to explore whether TAS could influence NLPR3
inflammasome activation in macrophages. The results showed that TAS dose-dependently suppressed the activation of caspase-1 in
lipopolysaccharide (LPS)-primed murine primary macrophages upon
nigericin treatment, resulting in reduced mature interleukin-1β (IL-1β) release and gasdermin D (GSDMD) cleavage. TAS greatly reduced ASC speck formation upon the stimulation of
nigericin or extracellular
ATP. Consistent with reduced cleavage of GSDMD,
nigericin-induced pyroptosis was alleviated by TAS. Interestingly, TAS time-dependently suppressed the mechanistic target of
rapamycin (mTOR) complex 1 (
mTORC1) and
mTORC2 signaling induced by LPS priming. Like TAS, both INK-128 (inhibiting both
mTORC1 and
mTORC2) and
rapamycin (inhibiting
mTORC1 only) also inhibited NLRP3
inflammasome activation, though their effects on mTOR signaling were different. Moreover, TAS treatment alleviated mitochondrial damage by
nigericin and improved mouse survival from
bacterial infection, accompanied by reduced IL-1β levels in vivo. Collectively, by inhibiting the NLRP3
inflammasome activation, TAS displayed anti-inflammatory effects likely through regulation of the mTOR signaling in macrophages, highlighting a potential action mechanism for the anti-inflammatory activity of Dandelion in treating
inflammation-related disorders, which warrants further clinical investigation.