CD24分子调控急性肝损伤的细胞基础及分子机制的研究

Immunological regulation of acute liver injury is one of the major topics in present immunological and liver disease research areas. CD24, also known as the heat-stable antigen (HSA), is expressed as a glycosyl-phosphatidyl-inositol (GPI)-anchored molecule. However，how CD24 is associated with liver injury and its cellular and molecular mechanisms remain unresolved. More recently, we have found that administration of anti-CD24 antibody causes rapid death of wild-type (WT) mice-induced by pertussis toxin (PTX) with 12 hours, which is accompanied by increased amounts of serum alanine transaminase (ALT), aspartate aminotransferase (AST) and liver hemorrhage. We also have detected a massive increase in the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) after purtussis toxin and anti-CD24 antibody treatment. To test whether the absence of T and B cells can affect these results, we repeated these previous experiments using Rag-/- mice, and found all of these indicatives of liver damage keeping the similar results. Based on these discoveries, we hypothesize that CD24 may serve as an important negative regulator for acute liver injury, which expresses on the surface of one or several kinds of the innate immune cells in the liver, inhibits immune response and inflammation, and protects the host against attack of foreign pathogens and its derivatives. Therefore, we will try to solve the following key scientific questions: 1) what is the role of CD24 in acute liver injury? 2) how does CD24 distribute in liver? 3) what is the molecular mechanisms of CD24 regulating acute liver injury. Our proposed studies may not only contribute to clarify the role of CD24 in the regulation of acute liver injury, but also to deepen the understanding of the pathogen-induced inflammatory response in the host's liver, furthermore uncover new drug targets for the clinical treatment of liver diseases.

急性肝损伤的免疫调节是当今免疫学和肝病研究的重大课题之一。CD24分子是一种具有免疫调节作用的糖基化磷脂酰肌醇锚定分子，其发挥调节作用的机制尚不清楚。我们发现：anti-CD24中和抗体能加重小鼠肝损伤，表现为小鼠死亡率升高、谷丙转氨酶等肝功能指标以及小鼠TNF-a 明显增加。利用Rag1-/-小鼠，重复上述实验没有发现明显改变。因此，我们假设：CD24分子可能是急性肝损伤的一个重要负反馈调节分子，通过调节肝内固有免疫反应如Kupffer细胞等固有免疫细胞来阻止急性肝损伤的发生。本研究中我们试图解决如下几个关键的科学问题：1）肝内CD24表达与急性肝损伤的关系；2）CD24在肝内的细胞学分布；3）CD24分子调节急性肝损伤的细胞学基础和相关分子机理。本研究有助于系统阐明CD24分子调控急性肝损伤的免疫学机制，加深病原体在宿主肝内炎症反应调节机制的理解，为肝病治疗寻找新的药物靶点。

CD24 分子是一种具有免疫调节作用的糖基化磷脂酰肌醇锚定分子，其发挥急性肝损伤调节作用的机制尚不清楚。我们经一年的研究发现：anti-CD24 中和抗体与百日咳毒素联合注射能够引起小鼠急性肝损伤，表现为小鼠死亡率升高、谷丙转氨酶等肝功能指标明显升高；HE染色发现死亡小鼠肝脏和脾脏出血等病理性改变；流式分析发现：百日咳毒素刺激能够引起小鼠腹腔巨噬细胞和肝脏Kupffer细胞CD24分子的表达增加，免疫组化也证实了这一结果。因此，我们初步认为：CD24 分子是急性肝损伤的一个重要负反馈调节分子，通过调节肝内固有免疫反应如Kupffer 细胞等固有免疫细胞来阻止急性肝损伤的发生。在下一阶段的研究中我们试图解决如下关键的科学问题：1）CD24 在肝内的细胞学分布；2）CD24 分子调节急性肝损伤的细胞学基础和相关分子机理。本研究有助于系统阐明CD24 分子调控急性肝损伤的免疫学机制，加深病原体在宿主肝内炎症反应调节机制的理解，为肝病治疗寻找新的药物靶点。