NLRP3炎症体在慢性乙型肝炎病毒感染所致肝脏炎症与纤维化机制中的作用

NLRP3 is a multi-protein complex, belongs to NOD-like receptors family, which are important members of pattern recognition receptors of innate immunity. NLRP3 could sense the signals of intracellular pathogen products and metabolic stress. When be activated, it may split the pro-caspase-1 to the mature form of caspase-1. The latter will further activate interleukin-1beta and interleukin -18, and inactivate interleukin-33, which induces or amplify the inflammatory response. Studies showed NLRP3 played a key role in viral diseases caused by Infuenza virus, Rotavirus and others. On the other hand, NLRP3 was suggested to be associated with a variety of liver diseases, including fatty liver diseases, hepatitis C, and so on. And NLRP3 was proved to take part in the process of liver fibrosis and cirrhosis. However, to date, the role of NLRP3 during hepatitis B virus(HBV) infection is still unknown. This program was designed to disclose the mask of NLRP3 in the pathogenesis of chronic hepatitis B(CHB).Firstly, in vitro experiments with hepatocellular cell lines or primary liver cells were used to test whether HBV infection up-regulates NLRP3 expression. Then, animal model of woodchuck hepatitis virus infected Chinese tree shrew and cross-sectional studies of CHB patients were used to explore the relationship bwtween NLRP3 and liver inflammation and fibrosis. Furthermore, silencing NLRP3 by RNA interference was applied to assess the protective effect of liver injury, and the NLRP3 siRNA vector will be built to search for new therapeutic targets of hepatitis B.

NLRP3炎症体是一种多蛋白复合物，属于NOD样受体家族，为固有免疫中模式识别受体的重要成员。NLRP3能感受胞内病原微生物产物及代谢性应激，其被激活后可活化Caspase-1，后者可进一步激活IL-1b和IL-18，并灭活IL-33，从而引起机体的炎症反应。研究表明，NLRP3参与了流感病毒、腺病毒等多种病毒感染引起的炎症反应，且与脂肪性肝病、丙型肝炎等多种肝病有关，并且参与肝纤维化的调节。然而，NLRP3在HBV感染导致的慢性肝病中的作用却未见报道。为了探索NLRP3炎症体在慢性乙型肝炎发病机理中的作用，本课题拟首先通过体外细胞试验明确HBV感染是否上调肝细胞NLRP3基因表达，然后通过土拨鼠-WHV动物模型和人群横断面研究探讨NLRP3炎症体与肝脏炎症和纤维化的关系，最后应用RNA干扰技术沉默NLRP3基因观察其对肝脏疾病的保护作用，并探索基于NLRP3信号通路的乙型肝炎治疗靶点。

NLRP3炎症体是一种多蛋白复合物，属于NOD样受体家族，为固有免疫中模式识别受体的重要成员。NLRP3能感受胞内病原微生物产物及代谢性应激，其被激活后可活化Caspase-1，后者可进一步激活IL-1b和IL-18，并灭活IL-33，从而引起机体的炎症反应。NLRP3在HBV感染导致的慢性肝病中的作用尚未明确。为了探索NLRP3炎症体在慢性乙型肝炎发病机理中的作用，首先通过体外细胞试验明确HBV感染不会改变肝癌细胞系HepG2和单核细胞系THP的NLRP3基因表达，但体外感染人原代肝脏细胞可轻度上调NLRP3基因。然后，通过动物模型和人群横断面研究同样证实单纯HBV感染不会上调NLRP3及相关基因表达，但NLRP3炎症体明显参与肝脏炎症和纤维化活动，并且与其严重程度密切相关。最后，应用RNA干扰技术观察到沉默NLRP3基因对肝脏炎症活动具有一定保护作用。因此，基于 NLRP3信号通路的靶点可能成为治疗乙型肝炎的新方法。