Geraniol ameliorates acute liver failure induced by lipopolysaccharide/D-galactosamine via regulating macrophage polarization and NLRP3 inflammasome activation by PPAR-γ methylation Geraniol alleviates acute liver failure

Geraniol (Ger), a natural acyclic monoterpene alcohol, has been reported to exert protective effects through anti-inflammation in Acute liver failure (ALF). However, its specific roles and precise mechanisms underlying anti-inflammatory effects in ALF have not yet fully explored. We aimed to investigated the hepatoprotective effects and mechanisms of Ger against ALF induced by lipopolysaccharide (LPS)/D-galactosamine (GaIN). In this study, the liver tissue and serum of LPS/D-GaIN-induced mice were collected. The degree of liver tissue injury was evaluated by HE and TUNEL staining. Serum levels of liver injury markers (ALT and AST) and inflammatory factors were measured by ELISA assays. PCR and western blotting were conducted to determine the expression of inflammatory cytokines, NLRP3 inflammasome-related proteins, PPAR-γ pathway-related proteins, DNA Methyltransferases and M1/M2 polarization cytokines. Immunofluorescence staining was used to assess the localization and expression of macrophage markers (F4/80 and CD86), NLRP3 and PPAR-γ. In vitro experiments were performed in macrophages stimulated with LPS with or without IFN-γ. Purification of macrophages and cell apoptosis was analyzed using flow cytometry. We found that Ger effectively alleviated ALF in mice, specified by the attenuation of liver tissue pathological damage, inhibition of ALT, AST and inflammatory factor levels, and inactivation of NLRP3 inflammasome. Meanwhile, downregulation M1 macrophage polarization may involve in the protective effects of Ger. In vitro, Ger reduced the activation of NLRP3 inflammasome and apoptosis through regulating PPAR-γ methylation by inhibiting M1 macrophage polarization. In conclusion, Ger protects against ALF through suppressing NLRP3 inflammasome-mediated inflammation and LPS-induced macrophage M1 polarization via modulating PPAR-γ methylation.