S100A8/A9介导的炎症小体活化对免疫炎症的影响及其作用机制研究

S100A8/A9, also known as myeloid-related protein 8/14 (MRP8/14), participates in regulating a variety of pathogens-mediated inflammatory response. However, it is still unknow how MRP8/14 regulates infection-mediated inflammation. Our preliminary studies revealed that MRP8/14 expression was significantly upregulated after bacteria infection, and it also closely associated with the development and outcome of inflammation. To determine the molecular mechanisms involved in MRP8/14-mediated inflammatory response, further preliminary studies have been performed and indicated that MRP8/14 regulated the balance and development of inflammation through activation of inflammasome induced by infection. Based on these preliminary data, we hypothesized that the activation of MRP8/14-mediated inflammasome regulates the balance of immune inflammation. That is, after infection of pathogens, MRP8/14 promotes the production of IL-1β, IL-18 and IL-33 by activating inflammasome. The inflammatory cytokines modulate the helper T cells to secrete Th1/Th2 cytokines, which regulates the balance of inflammation and attenuates immuno- pathogenesis cuased by over inflammation. To test our hypothesize and uncover the new mechanisms of MRP8/14 in regulating inflammation, both in vivo and in vitro experiments will be used to provide a reliable theoretical basis for seeking a new target for the treatment of inflammation, and developing new clinical treatment strategies for inflammatory diseases.

S100A8/A9又名髓样相关蛋白8/14（MRP8/14），参与调控多种病原体感染导致的炎症反应，但其在炎症反应中的作用及其机制仍然不清。预实验显示，细菌感染后MRP8/14表达显著上调且与炎症的发生发展密切相关。那么，MRP8/14介导免疫炎症的机制是什么？进一步实验发现，感染后MRP8/14通过激活炎症小体而调控免疫炎症的平衡和发展。据此，我们首次提出"MRP8/14通过炎症小体活化调控免疫炎症平衡"假说，即：病原体感染后，MRP8/14激活炎症小体，促进IL-1β、IL-18、IL-33产生，调控辅助T细胞分泌Th1/Th2细胞因子，从而调控免疫炎症平衡，抑制过度炎症导致的免疫病理损害。本课题拟通过体内、体外实验，揭示MRP8/14介导的炎症小体调控免疫炎症的新机制，为寻找炎症治疗新靶点，开发针对炎症性疾病的临床诊治新策略提供可靠的实验依据。

本项目提出了“MRP8/14通过激活NF-κB通路以及促进ROS产生，活化炎症小体，诱导IL-1β、IL-18和IL-33分泌，从而调控Th1/Th2型细胞因子的产生，最终使免疫炎症处于动态平衡（Th1/Th2平衡）”的科学假说，围绕MRP8/14在调控胞内菌、胞外菌或病毒感染介导的免疫炎症平衡的作用及其机制，进行了系列研究，取得的主要成果包括：.1. 发现胞内菌（结核分枝杆菌-BCG）感染人单核源性巨噬细胞（MDMs）或THP-1细胞后，MRP8/14的mRNA和蛋白表达水平均明显上调（Journal of Infection, 2015）。.2. 证实MRP8/14被敲低后，MDMs和THP-1细胞对BCG的杀伤作用均受到了抑制（Journal of Infection, 2015）。.3. 阐明MRP8/14通过促进ROS产生而诱导细胞自噬，增强THP-1细胞清除BCG的作用及其机制（Journal of Infection, 2015）。.4. 基于我们前期研究发现胞外菌（绿脓杆菌-PA）感染能够上调MRP8/14的表达，本研究进一步证实PA感染MDMs后能够激活NLRP3炎症小体，促进caspase-1活化和IL-1β产生（Infection and Immunity, 2016）。.5. 发现NLRP3炎症小体活化产生的IL-1β，通过诱导细胞自噬，从而抑制巨噬细胞对PA的杀伤作用（Infection and Immunity, 2016）。.6. 发现活动性肺结核患者外周血中，髓样细胞触发受体-1（TREM-1）+的Vδ2 T细胞亚群的比例明显上调，且TREM-1促进Vδ2 T细胞对BCG的吞噬和杀伤（Journal of Immunology, 2018）。.7. 证实活动性结核感染后，TREM-1+ Vδ2 T细胞可促进CD4+效应T细胞的增殖和分化，并增加Th1型细胞因子IFN-γ的产生（Journal of Immunology, 2018）。.8. 阐明小鼠巨噬细胞感染BCG后，通过分泌IL-1β，介导间充质干细胞（MSC）NF-κB和JAK-STAT1信号通路活化，促进NO产生和结核菌清除（Scientific Reports, 2016）。.9. 证实登革病毒感染MDMs后，MRP8/14的mRNA和蛋白表达水平均明显下调。