Bardoxolone methyl alleviates acute liver injury in mice by inhibiting NLRP3 inflammasome activation
Objective To investigate the inhibitory effect of bardoxolone methyl(CDDO-Me)on activation of NLRP3 inflammasome and its mechanism for alleviating acute liver injury(ALI).Methods Mouse bone marrow-derived macrophages(BMDM)and THP-1 cells were pre-treated with CDDO-Me followed by treatment with Nigericin,ATP,MSU,intracellular LPS transfection for activation of NLRP3 inflammasomes,or poly A:T for activation of AIM2 inflammasomes.The levels of caspase-1 and IL-1β in the cell culture supernatant was determined with Western blotting and ELISA to assess the inhibitory effect of CDDO-Me on NLRP3 inflammasomes and its specificity.In the animal experiment,male C57BL/6J mouse models of acetaminophen-induced ALI were treated with low-dose(20 mg/kg)and high-dose(40 mg/kg)CDDO-Me,and the changes in serum levels of IL-1β,TNF-α,AST and ALT were measured by ELISA and liver tissue pathology was observed using HE staining.Results In mouse BMDM and THP-1 cells,CDDO-Me dose-dependently inhibited the activation of NLRP3 inflammasomes without significantly affecting the secretion of non-inflammasome-related inflammatory factors IL-6 and TNF-α or AIM2 inflammasome activation.In the mouse models of ALI,CDDO-Me treatment at both the low and high doses significantly reduced serum levels of IL-1β,AST and ALT,ameliorated histological changes and reduced inflammatory cell infiltration in the liver tissue,and the effects exhibited a distinct dose dependence.Conclusion CDDO-Me can specifically inhibit the activation of NLRP3 inflammasomes to alleviate acetaminophen-induced ALI in mice.
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