Evodiamine Augments NLRP3 Inflammasome Activation and Anti-bacterial Responses Through Inducing α-Tubulin Acetylation

Abstract

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.

The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

“…Therefore, SIRT2 acts as a negative regulator of NLRP3 inflammasome activity [27]. Consistent with this study, other groups also reported that blockade of acetylation or restoration of intracellular NAD + levels with various pharmaceuticals abrogates this phenomenon [127,128]. SIRT2 also removes acetyl groups from NLRP3 to block the complex assembly [129].…”

Evodiamine Attenuates Experimental Colitis Injury Via Activating Autophagy and Inhibiting NLRP3 Inflammasome Assembly

“…Shen et al also showed that activity of NLRP3 inflammasome was inhibited by evodiamine in mice colonic tissues ( Shen et al, 2019 ). Whereas Li et al reported that evodiamine promoted NLRP3 inflammasome activation in J774A.1 and bone marrow-derived macrophages (BMDMs) ( Li et al, 2019 ). Our data demonstrated that there was no significant alteration in NLRP3 expression.…”

Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling

“…Bone marrow-derived macrophages (BMDMs) were induced as previously reported 45 , with minor modification. Briefly, bone marrow cells were collected from hind femora and tibias of mice and differentiated in DMEM supplemented with 10% FBS and 20% macrophage colony-stimulating factor (M-CSF)-conditioned medium from L929 cells (BM-Mac medium) at 37 °C in a humidified incubator of 5% CO 2 .…”