IL-33/ST2L通路调节巨噬细胞极化促进肾间质纤维化的研究

Renal interstitial fibrosis results in the progress of chronic kidney disease (CKD).Macrophages are the essential cells in the development of renal interstitial fibrosis. Data show that IL-33/ST2L pathways induce the activation and polarization of macrophages, exacerbate diseases mediated by M2 macrophages immune response, and participate in tissue fiberosis mediated by chronic inflammatory response.The responses mediated by IL-33/ST2 pathway are similar to that of chronic inflammation,the accumulation of extracellular matrix,and renal interstitial fibrosis mediated by infiltrating macrophages into the renal tissue.Our results have shown that there are significantly elevated serum sST2 levels in the patients with CKD.Elevated serum sST2 levels are simultaneous with the enhancement of IL-33/ST2L pathways, which is the negative regulation and similar with a pulmonary fibrosis.Further research reveals that expression of ST2L on the macrophages is enhanced.Therefore,we speculate that IL-33/ST2L pathway participates in the process of renal interstitial fibrosis through regulating macrophages polarization.To substantiate this hypothesis, in the present study the effect of IL-33 on the expression and secretion of macrophages will be investigated.The impact of inflammatory factors released by macrophages on renal tubular epithelial cells will be discussed simultaneously. The effects of IL-33/ST2 pathway on renal macrophages and renal interstitial fibrosis will be investigated by using IL-33 antagonist and ST2 gene knockout mice.This study will provide new ideas and new targets of drug action for the effective prevention of renal interstitial fibrosis.

肾间质纤维化导致慢性肾脏病（CKD）进展，巨噬细胞是参与肾间质纤维化的关键细胞。IL-33/ST2L通路调节巨噬细胞激活与M2极化促进免疫反应疾病进展，参与炎症反应影响组织纤维增生，该通路介导的反应与肾脏巨噬细胞浸润导致慢性炎症、细胞外基质积聚及肾间质纤维化发生具有相似性。我们的研究证实CKD患者血清sST2明显增高，sST2增高是伴随IL-33/ST2L通路活性增强而出现的负向调节反应，该结果与肺纤维化类似，进一步研究显示单核巨噬细胞ST2L表达增强，因此推测“IL-33/ST2L通路可能通过调节巨噬细胞极化参与肾间质纤维化过程”。为证实假说，本文将观察IL-33处理的巨噬细胞表达变化及其炎症因子释放对肾小管上皮细胞的影响，应用IL-33拮抗剂、ST2基因敲除小鼠研究IL-33/ST2通路对肾脏巨噬细胞及间质纤维化的影响。本研究将为CKD肾间质纤维化的有效防治提供新思路和药物作用新靶点。

慢性肾脏病（Chronic kidney disease，CKD）是严重危害人类健康的重要疾病，具有患病率高、知晓率低、治疗费用高、心血管事件高危性以及早死等特点，该病的危害仅次于肿瘤和心脏疾病。肾间质纤维化在CKD进展至ESRD 的过程中具有核心作用，研究表明肾间质纤维化的严重程度与CKD 的肾功能进展具有高度相关性，控制肾间质纤维化是延缓CKD 进展至ESRD的关键，导致肾间质纤维化启动因素十分复杂，慢性炎症反应及免疫损伤是肾间质纤维化的重要因素，巨噬细胞是参与肾间质纤维化的关键细胞，资料表明IL-33/ST2L通路调节巨噬细胞激活与M2极化促进免疫反应疾病进展，参与炎症反应影响组织纤维增生，该通路介导的反应与肾脏巨噬细胞浸润导致慢性炎症、细胞外基质积聚及肾间质纤维化发生具有相似性。我们通过研究IL-33/ST2L通路调节巨噬细胞的M2方向极化，建立了稳定的IL-33细胞因子刺激巨噬细胞M2极化的模型，通过M2巨噬细胞刺激肾小管上皮细胞研究其表达标志物的变化，结果证实IL-33/ST2L通路通过调节巨噬细胞影响肾小管上皮细胞表达标志物的变化，能够使肾小上皮细胞发生间质转分化，体外研究结果证实IL-33/ST2L通路通过调节巨噬细胞促进肾小管上皮细胞间质转分化；同时我们建立UUO肾间质纤维化小鼠模型，以及应用抗ST2抗体干预肾间质纤维化小鼠研究IL-33/ST2通路对肾脏巨噬细胞及间质纤维化的影响，结果表明IL-33/ST2L通路参与肾脏巨噬细胞调节并促进肾间质纤维化。我们的研究从体内体外两个方面证实IL-33/ST2L通路、巨噬细胞与肾间质纤维化之间的联系，研究肾间质纤维化的可能机制，为控制肾间质纤维化的发生与发展，对防治CKD 进展具有重要意义，并为CKD肾间质纤维化的有效防治提供新思路和药物作用新靶点。