髓系细胞触发受体-1在IgA肾病中介导肾脏损伤的作用机制研究

IgA nephropathy is the most common primary glomerulonephritis, characterized by mesangial deposition of IgA-containing complex. Although the mechanism of renal injury in IgA nephropathy is still unclear today, we already know that the IgA-containing complex could activate mesangial cells and induce the secretion of a series of inflammation mediators, which lead to renal injury by distinct mechanisms. Our previous study suggested an upstream common regulatory mechanism for the production of these inflammation mediators. Accordingly, our preliminary experiment observed up-regulated expression of triggering receptor expressed on myeloid cells-1 (TREM-1) on mesangial cells under IgA-containing complex challenge. TREM-1 is an inflammation triggering receptor, who acts as an amplifier of inflammation after activation, through its induction of a series of inflammation mediators. TREM-1 was proved to be involved in many inflammatory diseases, while sTREM-1 as biomarkers for disease activity. Considering the inflammatory renal injury in IgA nephropathy and our previous findings, we proposed a pathogenic hypothesis of IgA nephropathy: IgA-containing complex could up-regulate the expression of TREM-1 in mesangial cells, which in turn induce the secretion of many inflammation mediators and at last lead to renal injury in IgA nephropathy. In the present study, in order to explore the underlying mechanism of TREM-1 in renal injury, we will at first evaluate our hypothesis in cultured mesangial cell models and then confirm it in patients with IgA nephropathy. We will also detect urinary sTREM-1 levels in patients with IgA nephropathy, to evaluate its predictive role for active inflammatory lesion in renal glomeruli.

IgA肾病是最常见的原发肾小球肾炎，IgA复合物的肾小球系膜区沉积是特征性表现，但沉积后肾脏损伤机制不明。已知IgA复合物会活化系膜细胞致多种炎症介质分泌，并发挥各自不同的肾损功能。申请者前期研究提示这些炎症介质分泌存在统一上游调控机制，并发现系膜细胞上调表达的髓系细胞触发受体-1（TREM-1）可能参与调控。TREM-1是炎症激发受体，活化后促进多种炎症介质合成，启动和放大炎症反应。TREM-1在多种炎症性疾病中起炎症放大器作用，其胞外可溶片段sTREM-1是炎症活动的标记物。基于IgA肾病免疫性炎症的特性和前期基础，申请者提出研究假设：IgA复合物通过上调系膜细胞TREM-1表达，发挥炎症放大效应，介导系列炎症介质分泌，致IgA肾病的肾脏损伤。本研究拟在体外细胞模型探讨TREM-1参与肾脏损伤的机制，并在IgA肾病患者中验证损伤机制，评估尿液sTREM-1对活动性炎症病变的提示作用。

IgA肾病是最常见的原发肾小球肾炎，IgA复合物的肾小球系膜区沉积是IgA肾病的特征性表现，但沉积后具体的肾脏损伤机制不明。已知在IgA1复合物导致肾脏损伤的过程中，炎症因子的产生是关键环节，如果对其加以调控，可以减轻IgA肾病的肾脏损伤、甚至阻断疾病发病及进展。本研究利用IgA肾病的体外细胞学模型，探讨了IgA肾病中肾脏局部的炎症损伤机制。本研究发现IgA肾病患者来源的致病性IgA复合物可上调系膜细胞TREM-1表达，由TREM-1介导炎症放大效应，引起多种炎症因子的上调分泌，导致后续肾脏炎症损伤。IgA肾病中系膜细胞活化后表达的MMP9可能剪切系膜细胞膜表面的TREM-1，是尿液sTREM-1水平升高的重要来源。我们的研究证实IgA肾病患者尿液sTREM-1水平显著升高，是IgA肾病潜在临床无创生物标志物。我们的研究发现揭示了IgA肾病的肾脏炎症损伤过程中的重要分子TREM-1，为后继炎症干预策略的建立提供潜在治疗靶点。此外，本研究还进一步探讨了致病性IgA1复合物中的有效致病成分，证实了致病性IgA1复合物中的抗糖抗体成分具有促进系膜细胞增殖的生物学效应，并建立了体外制备抗糖抗体-缺糖IgA1复合物的方法，利于未来体外IgA肾病细胞学模型的机制探讨。