炎性体ASC调控乙肝肝衰竭单核/巨噬细胞功能及相关机制研究

Liver failure, caused by HBV infection, lead to high mortality and its pathogenesis was still unclear. Recent data and our previous study showed monocyte/macrophage over activation in the early phase of liver failure contributed to generating a large amount of proinflammatory cytokines, which caused intense inflammatory response resulted in liver failure. Therefore, the inhibition of proinflammatory cytokines generation was the key point for blocking the occurrence of liver failure. ASC activation was the central step in several proinflammatory cytokines generation. Our preliminary study indicated that ASC expression was significantly reduced or even absent in peripheral monocytes of ACLF patients who recovered by liver-supporting system, compared to their baseline level. Prompt ASC may play an important role in the pathogenesis of liver failure; however, the detailed mechanism was still obscure. In this project, the expression and translocation of ASC in liver failure patients’ and related control group peoples’ monocyte/macrophage were measured. The regulating mechanism in the process of proinflammatory cytokines generation result from different location of ASC was explored through interventions in vitro. The feedback mechanism to ASC was also discovered. Liver failure mice model were established. The effect of ASC inhibition for lightening intense inflammatory response in liver was detected in vivo. We propose to provide experimental evidence for blocking the occurrence of liver failure.

乙肝引发的肝衰竭具有较高的病死率，而其发病机制仍不清晰。最新的证据及本项目组前期研究证实单核/巨噬细胞在肝衰竭早期过度活化并释放大量促炎因子，引起的强烈炎症反应会导致肝衰竭的发生。因此抑制过量炎症因子的产生是阻断肝衰竭发生的关键。炎性体ASC的激活是多种炎症因子产生的核心环节。我们的前期研究发现，人工肝治疗后病情显著改善的慢加急肝衰竭患者外周血单核细胞内ASC的表达与治疗前相比，表达较低甚至不表达。提示ASC在肝衰竭发生中起了重要作用，但机制尚不清楚。在本项目中，我们拟分析乙肝肝衰竭患者及相关对照组人群单核/巨噬细胞中ASC的表达水平及其转位情况；通过体外干预手段，探究胞内和胞外不同形式的ASC对单核/巨噬细胞产生促炎因子功能的调控机制，以及产物促炎因子对ASC的反馈调节作用；制备小鼠肝衰竭模型，体内检验干预ASC的激活来减轻肝脏过度炎症反应的效果，为寻找肝衰竭治疗的新靶点。

乙肝引发的肝衰竭具有较高的病死率，而其发病机制仍不清晰。本项目首先通过对乙肝肝衰竭患者及相关对照组人群单核/巨噬细胞中ASC的表达水平及其转位情况进行分析，发现慢加急肝衰竭患者外周血单核细胞中的ASC表达水平高于健康人群；然而由于技术的不成熟，未了解到ASC的转位情况；然后通过体外干预ASC手段，探究到不同PAMP和DAMP信号刺激下，单核/巨噬细胞中促炎因子IL-1beta的产生均受到抑制；同时进一步的研究发现了一个全新的上游调控因子SMARCC1，它不但在剧烈的炎症反应中具有较高的表达水平，还通过调控ASC与Caspase-1的结合进而促进IL-1beta的产生。此外，该因子还在HBV复制和转录调控中起着重要的角色；我们还通过了体内检验干预ASC的激活来减轻肝脏过度炎症反应的效果，然而体内干预后的效果并不理想。本项目通过对乙肝肝衰竭发病机制的探究和阐释，阐释了炎性体ASC在其中的重要作用，并首次发现了上游重要调控因子SMARCC1对促炎因子IL-1beta产生的必要因子，旨在寻找肝衰竭治疗的新靶点。