CARD9 调节APAP诱导的无菌性肝损伤和炎症的分子机制研究

Acetaminophen (N-acetyl-para-aminophenol, APAP) hepatotoxicity is the most common cause of death due to acute liver failure and is increasingly recognized as a significant public health problem. The initial event in APAP-induced hepatotoxicity is a toxic-metabolic injury leading to hepatocyte death by necrosis. This results in secondary activation of the innate immune response involving upregulation of inflammatory cytokines with activation of monocytes/macrophages and neutrophils. The adaptor protein Caspase Recruitment Domain-containing protein 9 (CARD9) is restrictedly expressed in myeloid cells and is the adaptor downstream of C-type lectin receptors (CLRs) for the sensing of fungal infection, but little is known about the clinical significance of CARD9 in non-infection/sterile inflammation diseases. Here we show that CARD9 exacerbate APAP hepatitis at the initiation of inflammation, and promote tissue recovery at the inflammation resolution phase. . This project will focus on the cellular and molecular mechanisms of how CARD9 regulate APAP induced hepatitis. We will use CARD9 conditional/ total knockout mice to study how CARD9 regulate sterile inflammation development (initiation and resolution phase) from three different levels which including molecular, cells and in vivo. This research will help to elucidate the new biological function and mechanisms of CARD9 in sterile inflammation progress, more importantly, this will shed light on investigating pathogenesis and some potential therapeutic approaches of drug induced liver injury.

对乙酰氨基酚(APAP)的过量服用是导致急性肝损伤的最主要因素，肝损伤的临床症状是综合了药物毒性和无菌炎症免疫损伤两方面的结果。中性粒细胞和单核/巨噬细胞作为肝损伤过程中最主要的细胞类型，参与肝脏的损伤和修复过程。已知CARD9在抗真菌感染中发挥重要，且主要表达在髓样细胞，但其在无菌炎症中的功能是未知的。我们的初步研究结果表明CARD9缺失小鼠在APAP诱导的肝损伤中表现出更好的生存率，在炎症消退期，CARD9则会促进组织的修复。. 本项目拟研究CARD9在APAP诱导的药物性肝损伤中的分子机制。运用CARD9相关的工具鼠，从分子、细胞到动物各个层面探讨CARD9在APAP导致的肝脏无菌炎症过程中损伤阶段和修复阶段的作用机制。这些问题的回答，将有助于阐明CARD9在无菌炎症起始和消退过程中新的调控机制，同时也为药物诱导的肝损伤治疗提供新的分子靶标和治疗策略。

在对乙酰氨基酚acetaminophen (APAP)诱导的肝损伤发生过程中，先天免疫细胞会导致组织损伤，同时也会加快组织的修复，但是，其中的细胞和分子机制却不是很清楚。已知CARD9在真菌感染中发挥着重要的功能，但是其在APAP导致的急性肝损伤中的功能却是未知的。我们使用了APAP的模型发现CARD9（在正常生理状态下主要表达在Kupffer细胞） 在前期会激活NF-kB的信号从而导致更强的炎症反应。而在后期单核细胞上表达的CARD9则会促进组织的修复。另外，我们发现可能是Kupffer细胞上表达的Trem2和单核细胞上表达的Mincle识别了死亡细胞释放的成分作为CARD9信号上游的受体发挥功能。