Exploration of the NLRP3 inflammasome as a key player in chronic liver disease

肝脏炎症是肝脏疾病的常见诱因，被认为是导致纤维化和肝细胞癌（HCC）的肝组织损伤的主要驱动因素。在西方国家，大多数慢性肝病（CLD）归因于慢性乙型和丙型肝炎感染、酒精消耗、代谢性疾病、药物/毒素诱导的肝损伤和自身免疫原因，包括免疫介导的胆道疾病。因此，慢性阻塞性肺病是一个严重的公共卫生负担，也是全世界死亡率和发病率的一个主要原因。炎性小体是一种细胞内多蛋白复合物，在肝脏实质细胞和非实质细胞中均有表达，是炎症和细胞命运的关键调节因子。研究最多的炎症小体NLRP3组装了一个由接头蛋白凋亡相关斑点样蛋白（ASC）和丝氨酸蛋白酶caspase-1组成的复合体。Nlrp3炎性小体通过激活caspase-1，释放il -1 β和IL-18，以及启动一种触发程序性细胞死亡的新途径（称为焦亡）来响应细胞危险信号。特别是NLRP3激活和IL-1信号传导与许多肝脏疾病的发病机制有关，包括：缺血-再灌注损伤、药物介导、病原体介导或内毒素介导的病理，以及NAFLD和肝纤维化。NLRP3炎性小体功能获得突变的作用最初被描述为一组罕见的自身炎症单基因疾病，称为冷冻素相关周期性综合征（CAPS）。随后，nlrp3炎性小体的多个基因多态性已被描述，其中一些与常见的慢性炎症有关，包括克罗恩病和类风湿性关节炎。特别是，影响15-20%普通人群的两种常见多态性，NLRP3中的Q705K和CARD8中的C10X，已被证明导致与疾病严重程度和il -1 β水平升高相关的功能获得表型。我们和其他人最近已经证明，NLRP3激活在实验性和人类肝脏疾病的肝脏炎症和纤维化中很重要。基于这些数据，我们提出了一个中心假设，即细胞特异性和时间特异性NLRP3炎性体激活是触发肝脏炎症、程序性细胞死亡、肝纤维化和最终肝硬化的中心机制。产生的关键问题分为三个目的：确定NLRP3炎性小体驱动的慢性炎症在纤维发生和肝纤维化中的作用。确定NLRP3启动的caspase-1激活、细胞因子产生和热噬细胞死亡在炎性小体驱动的慢性炎症、纤维化和肝纤维化发展中的作用。确定导致NLRP3炎性体功能获得表型的遗传变异的作用以及它们如何影响对慢性肝病的易感性。

Hepatic inflammation is a common trigger of liver disease, and is considered the main driver of hepatic tissue damage leading to fibrogenesis and hepatocellular carcinoma (HCC). In Western countries, most chronic liver diseases (CLD) are attributed to chronic hepatitis B and C infection, alcohol consumption, metabolic diseases, drug/toxin-induced liver injury and auto-immune causes, including immune-mediated biliary diseases. Therefore, CLD are a serious public health burden and are a major cause of worldwide mortality and morbidity. Inflammasomes, intracellular multi-protein complexes, are expressed in both parenchymal and non-parenchymal cells in the liver and severe as key regulators of inflammation and cell fate. The most studied inflammasome NLRP3 assembles a complex comprised of the adaptor protein apoptosis associated speck like protein (ASC) and the serine protease caspase-1. The Nlrp3 inflammasome responds to cellular danger signals by activating caspase-1, releasing IL-1beta and IL-18, as well as initiating a novel pathway triggering programmed cell death termed pyroptosis. In particular NLRP3 activation and IL-1 signalling have been implicated in the pathogenesis of many liver diseases including: ischemia-reperfusion injury, drug-mediated, pathogen-mediated, or endotoxin-mediated pathology, as well as NAFLD and liver fibrosis. A role for NLRP3 inflammasome gain-of-function mutations was initially described in a group of rare autoinflammatory monogenic conditions, termed cryopyrin-associated periodic syndromes (CAPS). Subsequently, multiple gene polymorphisms in the NLRP3-inflammasome have been described and some have been implicated in common chronic inflammatory conditions including Crohns disease and rheumatoid arthritis. In particular, two common polymorphisms affecting 15-20% of general population, Q705K in NLRP3 and C10X in CARD8 have been shown to result in gain-of-function phenotype associated with disease severity and increased IL-1beta levels. We and others have recently demonstrated that NLRP3 activation is important in hepatic inflammation and fibrosis in experimental and human liver disease. Based on these data we propose the CENTRAL HYPOTHESIS that cell- and time-specific NLRP3 inflammasome activation is a central mechanism that triggers hepatic inflammation, programmed cell death, and liver fibrogenesis and finally liver cirrhosis. The key questions generated are separated in three aims as follows: Determine the role of NLRP3 inflammasome driven chronic inflammation on fibrogenesis and liver fibrosis. Determine the role of NLRP3 initiated caspase-1 activation, cytokine production and pyroptotic cell death on the development of inflammasome driven chronic inflammation, fibrogenesis and liver fibrosis. Determine the role of genetic variations that result in NLRP3 inflammasome gain-of-function phenotypes and how they affect susceptibility to chronic liver disease.