从解毒祛瘀滋阴法下调PM2.5诱发的NET-pDC-IFN-α通路探讨其治疗SLE的作用与机制

Systemic lupus erythematosus (SLE) is a kind of life-threatening autoimmune disease characterized by inflammation of various tissues of the body. However, the pathogenesis of SLE is unclear yet. Preliminary studies indicated that there is a significant positive correlation between oxidative stress and the pathogenesis of SLE, while the Jieduquyuziyin method（typical recipe: Jieduquyuziyin recipe）can play a therapeutic role in the treatment of MRL/lpr mice through downregulation of hyperactive oxidative stress, but the further mechanism is still not fully understood. Fine particulate (PM2.5) is one of the important driving forces to produce hyperactive oxidative stress and lead to exacerbation of SLE. We would firstly study the PM2.5 exposure on SLE experiment mode administered with Jieduquyuziyin recipe, and clarify the function and mechanism of Jieduquyuziyin recipe through inhibiting high level ROS stimulated by PM2.5, thereby reducing the level of the NET-pDC-IFN-α pathway. Based on this, we would find Jieduquyuziyin recipe curative targets of SLE induced by PM2.5 exposure. Finally, the study will provide scientific basis for elucidating the mechanism of Jieduquyuziyin method in the treatment of SLE.

系统性红斑狼疮（SLE）是以免疫性炎症为突出表现并可危及生命的风湿免疫病，至今发病机制尚不完全清楚。本课题组前期研究发现，氧化应激与SLE发病之间存在显著正相关，而解毒祛瘀滋阴法（代表方解毒祛瘀滋阴方）可以通过下调SLE中亢奋的氧化应激水平发挥治疗作用，但作用机制有待进一步阐明。PM2.5作为致病外邪之一，是触发亢奋氧化应激并导致SLE发病加重的重要推手，本课题拟从解毒祛瘀滋阴方给药PM2.5染毒SLE实验模型出发，首次探究解毒祛瘀滋阴方通过降低PM2.5染毒产生的高水平ROS，抑制下游NET-pDC-IFN-α通路的作用与机制，并基于此发现解毒祛瘀滋阴方抑制PM2.5外邪诱发SLE的作用靶点，最终为阐明解毒祛瘀滋阴法治疗SLE的作用机制提供科学依据。

系统性红斑狼疮（SLE）是以免疫性炎症为突出表现并可危及生命的风湿免疫病，至今发病机制尚不完全清楚。PM2.5作为致病外邪之一，是触发亢奋氧化应激并导致SLE发病加重的重要推手。本课题从解毒祛瘀滋阴方给药PM2.5染毒SLE实验模型出发，探究解毒祛瘀滋阴方通过降低PM2.5染毒产生的高水平ROS，抑制下游NET-pDC-IFN-α通路的作用与机制。研究发现：(1)解毒祛瘀滋阴方能有效降低PM2.5诱发的红斑狼疮小鼠血清ds-DNA抗体水平、血浆IFN-α水平以及肺泡灌洗液中ROS含量；并且改善狼疮小鼠肺脏与肾脏的病理损坏，电镜观察到解毒祛瘀滋阴方组线粒体损害明显减少。解毒祛瘀滋阴方可能通过影响ROS-NETosis-IFN-α通路，发挥治疗PM2.5诱发的SLE作用；（2）解毒祛瘀滋阴方能够通过改善氧化应激水平，减少ROS产生，从而抑制NETs的生成，进而调控TLR9介导的NETosis过程，通过改善氧自由基对组织的炎症损伤，从而发挥对SLE的治疗作用；（3）解毒祛瘀滋阴方载药血清能抑制NET激活的树突状细胞（DLCs）TLR9-IFN-α信号通路相关mRNA及蛋白的表达，降低培养上清中IFN-α水平。本课题阐明解毒祛瘀滋阴方抑制PM2.5外邪诱发SLE的作用靶点，为解毒祛瘀滋阴法治疗SLE的作用机制提供科学依据。