重型肝炎mfgl2分子在肝脏Kupffer 细胞M1/M2极化和NK细胞活化中的调节作用及其机制

Severe hepatitis B (SHB)has a high prevalence in China which results in serious clinical outcomes with a death rate ranged 60-70%m. The pathogenesis of SHB has not been fully understood leading difficulty of clinical management and outcome prediction. Currently, it is widely accepted that liver as an innate immune dominant organ directly affects the occurrence, development and outcome of clinical diseases. Hepatic kupffer cell polarization between M1 cell and M2 cell contributes importantly to the clinical outcomes of many diseases. Nevertheless the role of kupffer cell polarization in pathogenesis and development of SHB has not been explored yet. Our previous study showed that activation of hepatic kupffer cell and NK cell played extraordinary role in progress of SHB. Hepatic kupffer cell might polarize from M2 to M1 in the process, and the polarizing M1 cell highly expressed membrane fgl2 (mfgl2) molecule, which indicates that mfgl2 may be a potential marker for M1 cell polarization. Hepatic kupffer cell with increased expression of fgl2 may further promote activation and function of hepatic NK cell. In this study, we will confirm the role of fgl2 in polarization of kupffer cell in SHB utilizing clinical samples, animal models and cell culture system and the related mechanism as whether mfgl2 as one of the molecular markers for M1 macrophages. Furthermore we will explore the contribution of mfgl2 highly expressed M1 cell in hepatic NK cell activation and function in this process. This study may provide a new therapeutic pathways or targets for future clinical intervention of SHB.

乙型重型肝炎仍是我国常见病,发病机制尚未完全阐明，是乙型重型肝炎病程难以预测和病死率高的根本。近期研究提示肝脏Kupffer细胞M1/M2极向转化对肝损伤的转归有着重要影响，但在乙型重型肝炎尚未见报道。我们前期研究发现， Kupffer细胞和其高表达跨膜型纤维介素（mfgl2）以及NK细胞的活化在乙型重型肝炎中起关键作用； Kupffer细胞存在M2→M1极向偏移，且向M1极化的巨噬细胞胞膜特异性高表达mfgl2分子，提示mfgl2分子可能是M1型巨噬细胞极化的一种表面标志；高表达mfgl2的Kupffer细胞可能促进肝NK细胞的活化与杀伤。据此，我们拟通过临床标本、动物模型和细胞实验，研究乙型重型肝炎中Kupffer细胞M2/M1型的极向偏移，明确mfgl2的作用（表面标志）及其机制，探明高表达mfgl2 的M1型Kupffer细胞对NK细胞活化调节作用及其机制，为临床干预提供新思路。

乙型重型肝炎仍是我国常见病,发病机制尚未完全阐明，是乙型重型肝炎病程难以预测和病死率高的根本。近期研究提示肝脏Kupffer细胞M1/M2极向转化对肝损伤的转归有着重要影响，但在乙型重型肝炎尚未见报道。我们前期研究发现， Kupffer细胞和其高表达跨膜型纤维介素（mfgl2）以及NK细胞的活化在乙型重型肝炎中起关键作用； Kupffer细胞存在M2→M1极向偏移，且向M1极化的巨噬细胞胞膜特异性高表达mfgl2分子，提示mfgl2分子可能介导M1型巨噬细胞极化参与乙型重型肝炎发病过程。本课题的主要实施内容、重要结果数据及科学意义如下：1、本研究在小鼠暴发性肝炎发展过程中发现随肝脏炎症加重，枯否细胞持续耗竭而外周单核细胞大量浸润至肝脏补充，且KCs和MoMFs均表现出促炎极化状态；2、本研究通过ACLF患者的肝组织、WT和fgl2-/-暴发性肝炎小鼠模型以及体外实验证实了fgl2分子具有调节肝脏巨噬细胞促炎极化的作用从而推动重型肝炎发生发展；3、本研究进一步揭示了fgl2通过调节NF-kB、MAPK及IRF3中蛋白磷酸化水平促进巨噬细胞促炎极化过程；丰富了巨噬细胞极化调节网络，为我们后续进一步研究肝病的治疗策略提供了理论基础。