miR-142调控NLRP3炎症小体参与成人斯蒂尔病发病的机制研究

Adult-onset Still’s Disease (AOSD) is a complex autoinflammatory disease of unknown etiology. Non-coding small RNAs (microRNAs) have recently been identified as important regulators of inflammatory and autoimmune diseases. However, it is still unknown whether microRNA plays a role in the pathogenesis of AOSD. In the current study, we found that both miR-142-3p and -5p were significantly downregulated in the peripheral blood monocytes of AOSD patients compared to the healthy controls. Moreover, the miR-142-3p/5p expression levels were negatively associated with the disease activity markers of AOSD. IL-18 and IL-1β, processed through the inflammasome machinery, especially NLRP3 inflammasome, play key roles in the pathogenesis of AOSD. The expression of IL-18 and IL-1β are increased in the serum of AOSD patients. We found that overexpression of mir-142-3p/5p can inhibit the expression of NLRP3, Caspase-1, IL-18 and IL-1β. Through bioinformatic analysis, we speculate that mir-142-3p/5p may regulate the activity of NLRP3 inflammasome by targeting FBXO3 gene. Thus, this project is aimed to explore the function of miR-142-3p/5p in AOSD, exploring the signaling pathways of NLRP3 inflammasome regulated by miR-142-3p/5p in monocytes, macrophages and miR-142 knockout mice, thereby supplying evidence of miR-142 involving in the pathogenesis of AOSD. Thus miR-142 may represent as a potent AOSD diagnosis marker and treatment target.

成人斯蒂尔病(AOSD)是一种复杂的机制不明的自身炎症性疾病。我们探索了microRNA在AOSD发病中的作用，发现miR-142-3p和-5p在活动期AOSD患者单核细胞中表达下调，并和疾病活动性负相关。参与AOSD发病的关键性炎症因子IL-1β和IL-18在患者血清中表达升高，这两个炎症因子的产生依赖于NLRP3炎症小体的激活。我们发现过表达miR-142-3p和-5p可以抑制NLRP3及下游Caspase-1的蛋白表达水平。通过生物信息学分析，我们推测miR-142-3p和-5p可能通过靶基因FBXO3影响NLRP3炎症小体的活性及IL-1β和IL-18的表达。本项目旨在通过细胞实验及miR-142敲除小鼠，探究miR-142通过调控FBXO3激活NLRP3炎症小体，促进下游IL-1β和IL-18的表达参与AOSD发病的新机制，为寻找AOSD新的临床诊断标志物及治疗靶点提供理论依据。

成人斯蒂尔疾病（AOSD）是一种复杂的病因未明的自身炎症性疾病。本研究以microRNA为切入点，探索miR-142调控NLRP3炎症小体参与AOSD发病的机制。我们发现miR-142-3p和-5p在活动期AOSD患者中表达下调，并和疾病的活动性评分等指标存在负相关性。参与AOSD发病的关键性炎症因子IL-1β和IL-18在患者血清中表达升高，这两个炎症因子的产生依赖于NLRP3炎症小体的激活。我们发现，过表达miR-142可以下调NLRP3和Caspase-1的蛋白表达水平，抑制IL-1β和IL-18的分泌水平。进一步机制研究发现，miR-142可能通过负调控其下游靶基因FBXO3，进而抑制FBXL2对NLRP3的降解作用，导致NLRP3炎症小体激活。本研究提出了"miR-142通过负调控FBXO3激活NLRP3炎症小体，促进下游IL-1β和IL-18的表达参与AOSD发病”的这一新机制，为探索AOSD更有效的治疗手段提供理论和实验依据。. 此外，受国自然的资助，我们围绕AOSD也开展了一些探索性研究。我们发现了血清sTREM-1水平升高是AOSD慢性病程的潜在预测分子，为早期判断疾病的预后带来了曙光；阻断TREM-1可以下调AOSD患者中性粒细胞及单核细胞炎症因子的分泌，TREM-1通路有望成为新的治疗靶点；发现了抗炎性细胞因子IL-10在AOSD中反馈性上调，纠正了以往的主流观点，IL-10有望成为新的疾病活动性标志物；还发现了疾病缓解期的血清标志物Cyr61。在临床研究方面，围绕AOSD疾病复发的特征及预后、肝脏受累的特征及预后、AOSD妊娠的结局及妊娠对疾病的影响及AOSD患者的心理状况和生活质量等开展了一系列的临床研究，以期待全方面了解AOSD疾病的临床特征，找到早期提示其不良预后的因素。