Resveratrol Alleviates Liver Fibrosis by Targeting Cross-Talk Between TLR2/MyD88/ERK and NF-κB/NLRP3 Inflammasome Pathways in Macrophages

Abstract

Resveratrol alleviates liver fibrosis in mice by upregulating IL-10 to reprogram the macrophage phenotype; however, the mechanism remains to be elucidated. Building on our previous work, in this study, we aimed to determine the role of the TLR2/MyD88/ERK and NF-κB/NLRP3 inflammasome pathways in mediating the effects of resveratrol on liver fibrosis and macrophage polarization. We investigated the expression of cytokines in these inflammasome pathways in a mouse model of liver fibrosis and resveratrol-treated macrophages. The results showed that expression of TLR2, MyD88, ERK, and NF-κB1 in liver tissues was increased in the fourth week after treatment with resveratrol but decreased in the fifth week. Similar results were obtained for the NF-κB/NLRP3 inflammasome pathway. The results also showed that cytokines in both the TLR2/MyD88/ERK and NF-κB/NLRP3 inflammasome pathways in macrophages were elevated after 24 h and reduced after 36 h of treatment with resveratrol. Immunofluorescence and nucleocytoplasmic separation assays showed that resveratrol inhibited the translocation of NF-κB from the cytoplasm to the nucleus in macrophages, and increased NF-κB1 was associated with inhibition of the TLR2/MyD88/ERK pathway. Silencing NF-κB1 increased the expression of TLR2, MyD88, and ERK. In conclusion, the TLR2/MyD88/ERK and NF-κB/NLRP3 inflammasome pathways are involved in the effect of resveratrol on macrophage polarization and the subsequent modulation of liver fibrosis. NF-κB1 acts as the common cytokine that coordinates the crosstalk between the two pathways. Our findings highlight the potential of the members of these pathways as therapeutic targets toward the treatment of liver fibrosis.