中性粒细胞胞外陷阱(NETs)负向调控尿酸钠晶体诱导炎症反应的效应及机制

Damage-associated molecular patterns (DAMPs) released from injured tissues and cells are danger signals that lead to induce inflammatory damage and innate immune response. To clarify regulatory mechanisms of autoimmune response and inflammatory damage caused by DAMPs will provide new strategies for the diagnosis and treatment of a variety of chronic inflammatory diseases. The aim of this project is to explore negative targets and mechanism of regulating DAMPs-induced inflammation. In our obtained preliminary results, it was found that neutrophils in response to stimulation of monosodium urate (MSU) crystal, a kind of DAMPs, result in formation of neutrophil extracellular traps (NETs). In addition, NETs showed novel potential function of inhibiting the development of inflammatory response surprisingly. On the basis of previous work, in order to investigate the role and mechanisms of NETs in regulating MSU crystal-induced inflammation, we will further observe that effect of MSU crystal-induced NETs on production and liberation of cytokines and chemokines, as well as function of immunological effector cells. Meanwhile, modulation mechanism of NETs formation induced by MSU crystal will be identified by regulating expression of toll like receptors, ATP and Fc gamma receptors on neutrophils, respectively. The research will highlight and make a significant contribution to the science field of DAMPs-induced inflammatory disorders. Furthermore, it may enlighten discovery of negative regulation target to maintain the balance of immune system.

组织和细胞损伤后所释放的损伤相关分子模式(DAMPs)是诱导无菌性炎症和固有免疫应答的危险信号。阐明DAMPs介导自身免疫反应引起炎症损伤的调节机制有助于为多种自身免疫性疾病提供新的诊治策略。本课题旨在探索DAMPs诱导炎症反应的负向调节靶点和机制。前期工作中，我们发现一种DAMPs-尿酸钠(MSU)晶体诱导炎症反应时刺激中性粒细胞形成中性粒细胞胞外陷阱(NETs)，而且NETs具有潜在的抑制炎症的功能。在既往工作基础上，我们将从NETs对MSU晶体诱导炎症因子表达、释放以及对免疫细胞功能影响方面，进一步探讨NETs负向调控MSU晶体诱导炎症反应的效应和机制。同时，通过观察调节Toll样受体、ATP及Fcγ受体对NETs形成的影响，阐明MSU晶体诱导NETs形成的调控机制。研究不仅将对DAMPs诱导炎症反应的研究领域产生重要科学贡献，而且可能对免疫平衡中负向调节靶点的发现有一定启示作用。

组织和细胞损伤后所释放的损伤相关性分子模式(DAMPs)是诱导无菌性炎症和固有免疫应答的危险信号。阐明DAMPs介导自身免疫反应引起炎症损伤的调节机制有助于为多种慢性炎症性疾病提供新的诊治策略。本课题旨在探索DAMPs诱导炎症反应的负向调节靶点和机制。在前期发现尿酸钠(MSU)晶体诱导炎症反应时可刺激中性粒细胞形成中性粒细胞胞外陷阱(NETs)，而且NETs具有潜在的抑制炎症的功能的基础上，本课题从NETs负向调控MSU晶体诱导炎症反应的效应，NETs负向调控MSU晶体诱导炎症反应的机制以及MSU晶体诱导NETs形成的调控机制进行了深入研究。研究发现：（1）不同细胞密度PMN诱导MSU晶体介导急性炎症的效应不同；（2）细胞密度高时MSU晶体刺激PMN形成聚集性NETs，降解细胞因子，促进炎症消退；（3）钙离子、活性氧以及ATP参与了MSU晶体诱导NETs形成的机制；（4）不同大小MSU晶体和纳米颗粒诱导NETs形成的效应不同，小纳米颗粒刺激PMN诱导活性氧依赖的NETs形成。课题完成了NETs负向调控MSU晶体诱导炎症反应的效应及机制，揭示NETs在负向调节炎症反应中潜在的作用，为晶体诱导的急性炎症以及相关的自身免疫性疾病，如痛风等的炎症发生和缓解的机制提供了科学依据。同时，初步阐明了晶体和固态颗粒诱导NETs形成的调控机制，为进一步发现晶体诱导无菌性炎症和机体维持免疫平衡的负向调控机制提供一定的启示作用。