Inflammasome Is Activated in the Liver of Cholestatic Patients and Aggravates Hepatic injury in Bile Duct-Ligated Mouse
Inflammasome Is Activated in the Liver of Cholestatic Patients and Aggravates Hepatic injury in Bile Duct-Ligated Mouse
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DOI：
10.1016/j.jcmgh.2019.12.008
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发表时间：
2020-01-01
影响因子：
7.2
通讯作者：
Boyer, James L.
中科院分区：
文献类型：
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作者：
Cai, Shi-Ying;Ge, Maoxu;Boyer, James L.
背景与目的：炎症在胆汁淤积性肝损伤的发病机制中起重要作用，但炎症体是否参与尚不清楚，这也是本研究的目的。方法：分析原发性胆道性胆管炎（n = 15）和原发性硬化性胆管炎（n = 15）患者肝脏中的基因表达。野生型（WT）和Caspase-1(-/-)（Casp1(-/-)）小鼠进行胆管结扎（BDL）或假手术7天。用胆汁酸处理小鼠肝细胞和巨噬细胞。结果：与健康对照组相比，胆汁淤积症患者肝脏中Caspase-1、NLRP1、NLRP3和IL-1 β显著升高（n = 9）。与Casp1(-/-) BDL小鼠相比，WT BDL小鼠血浆IL-1 β (826 vs 345 pg/ml)、ALT （674 vs 482 U/L）和ALP （900 vs 622 U/L）水平显著升高。Caspase-1仅在WT - BDL肝脏中被发现。肝脏组织学评估显示Casp1(-/-) BDL小鼠比WT BDL小鼠纤维化更多，肝脏羟脯氨酸含量和纤维化基因表达分析证实了这一点。免疫细胞分析显示，Casp(-/-) BDL肝脏中巨噬细胞比WT BDL肝脏中巨噬细胞更多。进一步的巨噬细胞表型表征表明，Casp(-/-) BDL肝脏中M2抗炎巨噬细胞较多，CD206阳性细胞较多，IL-4、CD163、Fizz1和IL-33表达较高。当小鼠肝细胞和腹腔巨噬细胞暴露于主要内源性胆汁酸（300 μ M TCA）的抑胆水平时，既没有检测到IL-1 β诱导，也没有检测到procaspase-1的裂解。结论：炎性小体会加重胆汁淤积性肝损伤，但胆汁酸不会直接激活炎性小体。
BACKGROUND & AIMS: Inflammation plays an important role in the pathogenesis of cholestatic liver injury, but it is unclear whether the inflammasome is involved and is the objective of this study.METHODS: Gene expression was analyzed in the livers of patients with primary biliary cholangitis (n = 15) and primary sclerosing cholangitis (n = 15). Bile duct ligation (BDL) or sham operation was performed in wild-type (WT) and Caspase-1(-/-)(Casp1(-/-)) mice for 7 days. Mouse hepatocytes and macrophages were treated with bile acids.RESULTS: Caspase-1, NLRP1, NLRP3 and IL-1 beta were significantly increased in the livers of cholestatic patients when compared to healthy control subjects (n = 9). Significantly higher levels of plasma IL-1 beta (826 vs 345 pg/ml), ALT (674 vs 482 U/L) and ALP (900 vs 622 U/L) were seen in WT BDL mice compared to Casp1(-/-) BDL mice. Caspase-1 cleavage was found only in WT BDL livers. Assessment of liver histology indicated more fibrosis in Casp1(-/-) BDL mice than in WT BDL mice, confirmed by analyses of liver hydroxyproline content and the expression of fibrotic genes. Profiling of immune cells revealed that there were more macrophages in Casp(-/-) BDL livers than in WT BDL livers. Further macrophage phenotype characterization indicated that Casp(-/-) BDL livers had more M2 anti-inflammatory macrophages evidenced by more CD206 positive cells and higher expression of IL-4, CD163, Fizz1 and IL-33. When mouse hepatocytes and peritoneal macrophages were exposed to cholestatic levels of major endogenous bile acids (300 mu M TCA), neither IL-1 beta induction nor procaspase-1 cleavage were detected.CONCLUSIONS: The inflammasome exacerbates cholestatic liver injury, but bile acids do not directly activate the inflammasome.