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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice
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NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice

机译：NLRP3炎症小体激活导致小鼠肝细胞凋亡，肝炎和纤维化

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Inflammasome activation plays a central role in the development of drug-induced and obesity-associated liver disease. However, the sources and mechanisms of inflammasome-mediated liver damage remain poorly understood. Our aim was to investigate the effect of NLRP3 inflammasome activation on the liver using novel mouse models. We generated global and myeloid cell-specific conditional mutant Nlrp3 knock-in mice expressing the D301N Nlrp3 mutation (ortholog of D303N in human NLRP3), resulting in a hyperactive NLRP3. To study the presence and significance of NLRP3-initiated pyroptotic cell death, we separated hepatocytes from nonparenchymal cells and developed a novel flow-cytometry-based (fluorescence-activated cell sorting; FACS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase 1 (Casp1)- and propidium iodide (PI)-positive cells. Liver inflammation was quantified histologically by FACS and gene expression analysis. Liver fibrosis was assessed by Sirius Red staining and quantitative polymerase chain reaction for markers of hepatic stellate cell (HSC) activation. NLRP3 activation resulted in shortened survival, poor growth, and severe liver inflammation; characterized by neutrophilic infiltration and HSC activation with collagen deposition in the liver. These changes were partially attenuated by treatment with anakinra, an interleukin-1 receptor antagonist. Notably, hepatocytes from global Nlrp3-mutant mice showed marked hepatocyte pyroptotic cell death, with more than a 5-fold increase in active Casp1/PI double-positive cells. Myeloid cell-restricted mutant NLRP3 activation resulted in a less-severe liver phenotype in the absence of detectable pyroptotic hepatocyte cell death. Conclusions: Our data demonstrate that global and, to a lesser extent, myeloid-specific NLRP3 inflammasome activation results in severe liver inflammation and fibrosis while identifying hepatocyte pyroptotic cell death as a novel mechanism of NLRP3-mediated liver damage. (Hepatology 2014;59:898-910).
机译：炎性体激活在药物诱导的和肥胖相关的肝病的发展中起着核心作用。然而，对于炎症小体介导的肝损伤的来源和机制仍知之甚少。我们的目的是使用新型小鼠模型研究NLRP3炎性体激活对肝脏的影响。我们生成了表达D301N Nlrp3突变（人NLRP3中D303N的直系同源物）的全局和髓样细胞特异性条件突变体Nlrp3敲入小鼠，导致NLRP3过度活跃。为了研究NLRP3引发的焦磷酸化细胞死亡的存在及其意义，我们从非实质细胞中分离了肝细胞，并开​​发了一种基于流式细胞术（荧光激活细胞分选; FACS）的新型策略，可以基于检测到的和定量的体内焦磷酸化。活跃的caspase 1（Casp1）-和碘化丙啶（PI）阳性细胞。通过FACS和基因表达分析在组织学上定量肝脏炎症。通过Sirius Red染色和定量聚合酶链反应评估肝星状细胞（HSC）活化的标志物来评估肝纤维化。 NLRP3激活导致生存期缩短，生长不良和严重的肝脏炎症。其特征为嗜中性浸润和HSC活化，胶原沉积在肝脏中。这些变化通过白介素-1受体拮抗剂anakinra的治疗而部分减弱。值得注意的是，来自全球Nlrp3突变小鼠的肝细胞显示出明显的肝细胞焦磷酸化细胞死亡，活性Casp1 / PI双阳性细胞增加了5倍以上。在没有可检测的焦磷酸化肝细胞死亡的情况下，髓样细胞限制的突变体NLRP3激活导致较不严重的肝表型。结论：我们的数据表明，总体上和程度较小的髓样特异性NLRP3炎症小体激活会导致严重的肝脏炎症和纤维化，同时将肝细胞焦磷酸化细胞死亡确定为NLRP3介导的肝损伤的新机制。 （Hepatology 2014; 59：898-910）。

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