狼疮病程中TLR7信号通过Dectin-3/CARD9轴调控MDSCs数量及功能的机制

Myeloid derived suppressor cells (MDSCs) are considered to have a significant inhibitory effect on T cells. However, it is puzzling that we and other scholars recently found that the number of MDSCs in SLE patients and lupus model mice increased significantly. We found that the number of MDSCs increased far earlier than T and B cells, and was positively correlated with the TLR-7 expression. The lupus symptoms induced by TLR-7 agonist was significantly alleviated in Dectin3-/- and CARD9-/- mice. Dectin-3 is mainly expressed in myeloid cells, which can recognize certain sugars that are common in organisms. Therefore, we hypothesized that TLR7 pathway activation stimulates Dectin3/CARD9 axis dependent sugar recognition by influencing the lupus microenvironment in SLE patients. Then MDSCs specific procedures start and lead to the lupus development by increasing the MDSCs accumulation and the function changes. This project will explore the importance of TLR7 signaling in the course of lupus disease by affecting dectin-3/CARD9 axis, and explain the mechanism of dectin-3/CARD9 regulating the number and function of MDSC. This will be benefit to raise the new ideas and strategies for the SLE occurrence and treatment .

髓系来源抑制性细胞（MDSCs）被认为具有显著抑制T细胞的特征。然而，困惑的是我们及其他学者近期发现 SLE 患者及模型小鼠中MDSCs的数量显著增多。我们在检测狼疮模型小鼠病程时发现，MDSCs的数量增加远早于T和B细胞，且与TLR-7正相关；TLR-7激动剂诱发的狼疮样表型在Dectin3-/-和CARD9-/-鼠中显著缓解。Dectin-3主要表达于髓系细胞，可识别生物体中普遍存在的某些糖类。故我们提出假说：SLE患者TLR7通路活化导致微环境的改变，可能激发Dectin3/CARD9信号轴对糖类的识别，启动MDSCs的特异性程序，从而增加MDSCs数量及改变MDSCs的功能，启动狼疮的发生发展。本项目将探讨狼疮病程中TLR7信号影响Dectin-3/CARD9轴的重要分子，阐述Dectin-3/CARD9调控MDSC数量及功能的机制，为 SLE发生及治疗提出的新思路和新策略。

系统性红斑狼疮(SLE)是一种典型的自身免疫病。髓源性抑制细胞（MDSCs）被认为具有显著抑制T细胞的特征。然而，我们在检测狼疮小鼠模型病程时发现，MDSCs的数量增加远早于T和B细胞，且与TLR-7正相关；在Dectin3-/-小鼠中TLR-7激动剂诱发的狼疮样表型不明显。Dectin-3主要表达于髓系细胞。本项目拟探讨狼疮病程中TLR7信号影响Dectin-3/CARD9轴的重要分子，阐述Dectin-3/CARD9调控MDSC数量及功能的机制，为 SLE发生及治疗提出的新思路和新策略。本项目的主要研究结果为：①确认Dectin3的表达与SLEDAI呈正相关，而Dectin3的缺失可减低MDSCs的增殖和调节功能；发现Dectin3缺失可平衡转录因子FoxO1介导的LOX-1+ M-MDSCs的积累和功能；提示LOX-1+ M-MDSCs的增加与SLE病情恶化有关，其可能是治疗SLE的潜在靶细胞。②发现在pristane诱导的狼疮小鼠模型中M-MDSCs的比例也增加；从pristane诱导的狼疮小鼠分离的M-MDSCs中转录因子IRF-8的表达水平明显增高，且 miR-451a可靶向IRF-8调控M-MDSC的分化；提示IRF-8/miR-451a通过AMPK/mTOR信号参与M-MDSC分化可能是狼疮发展过程中的新机制。③发现TLR7/IFN-α通过mTOR信号途径导致的MDSCs异常可促进Th17/Tregs失衡，而mTOR新型抑制剂INK128可通过降低MDSCs累积缓解狼疮症状;与传统的mTOR抑制剂雷帕霉素相比，INK128通过调控MDSC能更有效地促进Th17/Tregs平衡。综上所述，我们揭示了SLE发生及发展的新机制，为诊疗SLE提供了新视野和新策略。在本项目实施过程中，已发表标注本项目基金号的SCI收录论文13篇；培养6名博士研究生和2 硕士研究生。