Lei Jin-Qing, Xie Qing-Li, Li Qing-Ping, Qin Shan-Yu, Wu Jiao-Hua, Jiang Hai-Xing, Yu Bing, Luo Wei
Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Gastroenterology, the Second Affiliated Hospital of Guangxi Medical University, Nanning, China.
J Biochem Mol Toxicol. 2025 Mar;39(3):e70208. doi: 10.1002/jbt.70208.
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.
白藜芦醇通过上调白细胞介素-10来重编程巨噬细胞表型，从而减轻小鼠肝纤维化；然而，其机制仍有待阐明。基于我们之前的工作，在本研究中，我们旨在确定Toll样受体2（TLR2）/髓样分化因子88（MyD88）/细胞外信号调节激酶（ERK）和核因子κB（NF-κB）/NLRP3炎性小体途径在介导白藜芦醇对肝纤维化和巨噬细胞极化作用中的作用。我们在肝纤维化小鼠模型和白藜芦醇处理的巨噬细胞中研究了这些炎性小体途径中细胞因子的表达。结果显示，白藜芦醇处理后第4周，肝组织中TLR2、MyD88、ERK和NF-κB1的表达增加，但在第5周降低。NF-κB/NLRP3炎性小体途径也得到了类似结果。结果还显示，白藜芦醇处理24小时后，巨噬细胞中TLR2/MyD88/ERK和NF-κB/NLRP3炎性小体途径中的细胞因子均升高，而处理36小时后降低。免疫荧光和核质分离试验表明，白藜芦醇抑制巨噬细胞中NF-κB从细胞质向细胞核的转位，且NF-κB1的增加与TLR2/MyD88/ERK途径的抑制有关。沉默NF-κB1可增加TLR2、MyD88和ERK的表达。总之，TLR2/MyD88/ERK和NF-κB/NLRP3炎性小体途径参与了白藜芦醇对巨噬细胞极化的影响以及随后对肝纤维化的调节。NF-κB1作为协调这两条途径之间相互作用的共同细胞因子。我们的研究结果突出了这些途径成员作为肝纤维化治疗靶点的潜力。
