The selective NLRP3 inflammasome inhibitor MCC950 alleviates cholestatic liver injury and fibrosis in mice
The selective NLRP3 inflammasome inhibitor MCC950 alleviates cholestatic liver injury and fibrosis in mice
复制标题
选择性NLRP3炎症小体抑制剂MCC950减轻小鼠胆汁淤积性肝损伤和纤维化
DOI：
10.1016/j.intimp.2019.02.016
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发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Li, Kewei
中科院分区：
文献类型：
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作者：
Qu, Junwen;Yuan, Zhiqing;Li, Kewei
胆汁淤积在许多临床情况下都会发生，并会导致严重的肝脏疾病。小分子NLRP3抑制剂MCC950此前被证明具有抗炎作用。然而，这些效应还没有在淤胆性肝损伤中得到检验。本研究通过小鼠胆总管结扎(BDL)模型，研究NLRP3炎症体的作用，探讨MCC950对胆汁淤积性肝损伤的治疗作用及其分子机制。观察MCC950对肝组织学改变、肝损伤程度、中性粒细胞浸润、肝细胞死亡、炎性细胞因子水平及NLRP3炎症体表达的影响。本研究结果证实NLRP3组分在胆管梗阻时表达上调。MCC950可通过减少促炎细胞因子IL-1β和IL-18的产生，抑制中性粒细胞的浸润和肝细胞的死亡，从而明显减轻BDL所致的肝损伤。此外，MCC950显著抑制胆汁淤积性肝损伤时NLRP3的激活。此外，转录组分析表明，Toll样受体信号通路可能参与了MCC950对胆汁淤积性肝损伤的保护作用。综上所述，实验结果表明MCC950通过阻断NLRP3炎性小体的激活而对胆汁淤积性肝损伤和肝纤维化具有保护作用，其机制部分归因于抑制Toll样受体信号转导。本研究提示MCC950可能是治疗淤胆性肝损伤的一种有效的治疗策略。
Cholestasis occurs in many clinical circumstances and leads to severe liver disorders. MCC950, a small-molecule NLRP3 inhibitor, was previously shown to have anti-inflammatory effects. However, these effects have not yet been examined in cholestatic liver injury. This study aimed to investigate the role of NLRP3 inflammasome and test the therapeutic efficacy and molecular mechanisms of MCC950 in cholestatic liver injury through the common bile duct ligation (BDL) model in mice. The influence of MCC950 on histological changes, levels of liver damage, neutrophil infiltration, liver cell death, inflammatory cytokine levels, and NLRP3 inflammasome expression were examined. The results of the current study confirmed that NLRP3 components were up-regulated during bile duct obstruction. MCC950 treatment significantly alleviated BDL-induced liver injury by reducing production of the pro-inflammatory cytokines IL-1 beta and IL-18 and inhibiting neutrophil infiltration and hepatic cell death. Moreover, MCC950 significantly inhibited NLRP3 activation during cholestatic liver injury. In addition, transcriptome analysis indicated that Toll-like receptor signaling may be involved in the protective effects of MCC950 in cholestatic liver injury. In conclusion, experimental findings demonstrate that MCC950 exerted protective effects in cholestatic liver injury and liver fibrosis by blocking NLRP3 inflammasome activation and the mechanism was partially attributed to inhibition of Toll-like receptor signaling. The present study indicates MCC950 could potentially be an effective therapeutic strategy for the treatment of cholestatic liver injury.