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Evodiamine is a major ingredient of the plant Evodia rutaecarpa , which has long been used for treating infection-related diseases including diarrhea, beriberi and oral ulcer, but the underlying mechanism is unclear. Here we aimed to explore whether evodiamine influenced NLRP3 (NLR family, pyrin containing domain 3) inflammasome activation in macrophages, which is a critical mechanism for defending the host against pathogenic infections. We uncovered that evodiamine dose-dependently enhanced NLRP3 inflammasome activation in lipopolysaccharide-primed macrophages, as indicated by increased interleukin (IL)-1β production and caspase-1 cleavage, accompanied by increased ASC speck formation and pyroptosis. Mechanistically, evodiamine induced acetylation of α-tubulin around the microtubule organization center (indicated by γ-tubulin) in lipopolysaccharide-primed macrophages. Such evodiamine-mediated increases in NLRP3 activation and pyroptosis were attenuated by activators of α-tubulin deacetylase, resveratrol and NAD + , or dynein-specific inhibitor ciliobrevin A. Small interfering RNA knockdown of αTAT1 (the gene encoding α-tubulin N -acetyltransferase) expression, which reduced α-tubulin acetylation, also diminished evodiamine-mediated augmentation of NLRP3 activation and pyroptosis. Evodiamine also enhanced NLRP3-mediated production of IL-1β and neutrophil recruitment in vivo . Moreover, evodiamine administration evidently improved survival of mice with lethal bacterial infection, accompanied by increased production of IL-1β and interferon-γ, decreased bacterial load, and dampened liver inflammation. Resveratrol treatment reversed evodiamine-induced increases of IL-1β and interferon-γ, and decreased bacterial clearance in mice. Collectively, our results indicated that evodiamine augmented the NLRP3 inflammasome activation through inducing α-tubulin acetylation, thereby conferring intensified innate immunity against bacterial infection.

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.

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