肝X受体通过调控Th17分化参与原发性胆汁性肝硬化发病机制的研究

Primary biliary cirrhosis(PBC) is characterized with non-suppurative cholangitis. However, the mechanisms are not clear yet. Non-suppurative initiate pathogenesis of PBC in early stage. Nonetheless, the specific mechanism is unclear. Interestingly, we detected a lower expression of liver X receptors（LXR）with an imbalance of Treg/Th17 T cells. Additionally, LXRs are important in immunomodulatory, which could affect T cell differentiation and expression of related cytokines with sterol regulatory element-binding protein-1(SREBP-1). Therefore, we hypothesized that abnormality of LXRs may be essential to PBC. With liberal quantity of clinical samples and animal models of PBC, we aim to research the mechanism of LXRs in regulating inflammation of PBC in three levels, these are clinical level, animal models level and cell level. After triggering and inhibiting function of LXRs, we will observe the expression of SREBP-1、 Foxp3/RORγt、 IL-17、TNF-α and population of Treg/Th17, then study its association with the intrahepatic inflammatory response as well as immunopathology. Then, we will explore whether LXRs regulates the differentiation of Th17 and influences the balance of Treg/Th17 through the expression of Foxp3/RORγt, while SREBP-1 should be evaluated in this condition. By verifying these hypotheses, our project will provide novel insights into the pathogenesis of PBC, which may serve as a new theoretical basis for further identification of new therapeutic targets.

原发性胆汁性肝硬化（PBC）以非化脓性胆管炎为病理特点，非化脓性炎症是病变启动的初始阶段，但具体机制不明确。我们的前期研究发现，PBC时肝内肝X受体（LXR）低表达，且Treg/Th17比例失衡。由于LXR是免疫调控的关键分子，可经固醇元件结合蛋白-1（SREBP-1）影响T细胞分化及相关细胞因子的表达，因此我们推测LXR表达/功能异常可能是PBC时重要的致病因素。本项目拟从已有的大量临床标本及前期建立的PBC动物模型着手，从临床、动物、细胞三个层次，研究LXR在PBC炎症调控中的作用，并深入探索LXR通过SREBP-1影响Foxp3/RORγt的表达，进而调控Th17细胞分化、影响Treg/Th17平衡的作用机制。通过完成本项目，我们将从多层面证实LXR可能是PBC重要的致病因素，为LXR激动剂用于PBC的临床治疗提供新的理论依据。

原发性胆管炎（PBC，以前称为原发性胆汁性肝硬化）是一种淋巴细胞性非化脓性胆管炎，可发展为胆汁淤积性肝硬化，导致肝衰竭和死亡。前期研究发现，PBC时肝内肝X受体（LXR）低表达，且Treg/Th17比例失衡。由于LXR是免疫调控的关键分子，可经固醇元件结合蛋白-1（SREBP-1）影响T细胞分化及相关细胞因子的表达，因此我们推测LXR表达/功能异常可能是PBC时重要的致病因素。本项目经过临床、动物、细胞三个层次的研究证实：1)PBC患者肝内LXR低表达，Th17/Treg升高，LXR可在体内实验中显示出平衡Th17/Treg、降低肝内炎症的积极调控作用；2)LXR对Foxp3/RORγt的调控作用不是直接的，不可以直接地引起Treg/Th17的改变；3)PBC患者CD4+T淋巴细胞的Foxp3甲基化程度较正常人升高，改变CD4+T淋巴细胞的Foxp3甲基化程度可以直接的平衡Th17/Treg。本研究为PBC的发病机制提供了重要的数据，针对CD4+T细胞FoxP3甲基化的调控显示了精确治疗PBC炎症的潜力，这为未来PBC的预防和治疗提供了新的依据。