系统性红斑狼疮中G-MDSCs通过分泌S100A8/9促进TLR7介导的自身免疫反应的机制研究

As is known, the regulation of MDSCs in autoimmune diseases has been well defined. Recent studies showed that patients with SLE show a higher level of accumulation of MDSCs in blood compared with healthy control subjects and the percentage of MDSCs in PBMCs was positively correlated with the SLEDAI, which hint that MDSCs may participate in the pathogenesis of SLE. Of note, TLR7-mediated autoimmunity is critical for the pathogenesis of SLE. However, it’s still unknown whether MDSCs from SLE can regulate TLR7-mediated autoimmunity. Interestingly, we found that G-MDSCs from MRL/lpr lupus mice could not inhibit, but significantly promote the activation of TLR7 signaling pathway in macrophages, dendritic cells and B cells; G-MDSCs from MRL/lpr lupus mice showed higher levels of S100A8 and S100A9 compared with that from C57BL/6 mice, blocking S100A8 and S100A9 could markedly reverse the function of G-MDSCs on the activation of TLR7 signaling pathway. In the present research, we intend to carry out the following research: ① To clarify the role of G-MDSCs in the pathogenesis of SLE; ② To reveal the mechanism by which G-MDSCs from SLE promotes the activation of TLR7 pathway through secretion of S100A8/9; ③ To evaluate the effect of S100A8/9 differential expression in G-MDSCs on the pathogenesis of SLE. Through these above researches, we try to confirm our hypothesis that G-MDSCs from SLE promote TLR7-mediated autoimmune response. This study will provide new ideas and strategies for revealing the pathogenesis and treatment of SLE.

骨髓来源的抑制性细胞（MDSCs）在调控炎性反应和免疫耐受的平衡与转化中发挥重要作用。已知MDSCs在SLE患者外周血中比例显著升高，TLR7介导的自身免疫反应对SLE的发病至关重要，但目前仍不清楚MDSCs对TLR7通路活化的调控作用。我们在前期研究中意外发现狼疮粒细胞样MDSCs（G-MDSCs）不仅不能抑制，反而促进多种免疫细胞中TLR7通路的活化；狼疮G-MDSCs显著高表达S100A8/9，阻断S100A8/9能有效逆转其对TLR7通路的促进作用。本课题拟展开如下研究：①明确G-MDSCs在狼疮发病中的作用；②揭示狼疮G-MDSCs通过分泌S100A8/9促进TLR7通路活化的机制；③评估狼疮G-MDSCs中S100A8/9差异表达对狼疮小鼠发病的影响。以论证我们的观点：狼疮G-MDSCs促进TLR7介导的自身免疫反应。本课题将为揭示SLE的发病机制及治疗提供新思路和新策略。

髓系抑制性细胞（MDSCs）是一群在调控炎性反应和免疫耐受的平衡与转化中发挥重要作用的免疫细胞，人MDSCs标记为CD11b+CD33+HLA-DR-CD14/CD15+，小鼠MDSCs标志为CD11b+Gr1+。已报道MDSCs在SLE患者外周血中比例显著升高，TLR7介导的自身免疫反应对SLE的发病至关重要，但目前仍不清楚MDSCs对TLR7通路活化的调控作用。我们在前期研究中发现狼疮MDSCs能够促进多种免疫细胞中TLR7通路的活化；狼疮MDSCs显著高表达S100A8/9，阻断S100A8/9能有效逆转其对TLR7通路的促进作用。本项目结合动物模型、细胞水平研究及临床样本展开研究，明确了MDSCs在TLR7介导的自身免疫反应中的具体作用，阐明了狼疮MDSCs通过S100A8/9-IFN-γ信号轴促进TLR7通路活化的分子机制，揭示了狼疮MDSCs中S100A8/9差异表达对TLR7介导的自身免疫反应的影响。.主要研究结果如下：首先，在动物水平发现狼疮MDSCs显著加重TLR7激动剂咪喹莫特（IMQ）诱导的狼疮模型小鼠病情，并且过继转移狼疮MDSCs显著促进巨噬细胞和树突状细胞的活化；其次，在细胞水平发现狼疮MDSCs能够促进TLR7激动剂R848介导的巨噬细胞和树突状细胞的活化，利用RNA-seq测序技术筛选出在狼疮MDSCs中异常高表达的细胞因子——钙调蛋白S100A8/9，机制研究发现狼疮MDSCs通过分泌S100A8/9促进巨噬细胞和树突状细胞自分泌IFN-γ，IFN-γ协同TLR7通路促进巨噬细胞和树突状细胞的活化；最后，我们在动物水平发现缺失S100A8/9能够逆转狼疮MDSCs对TLR7激动剂IMQ诱导的狼疮模型小鼠的促进作用。本研究阐明了狼疮MDSCs促进TLR7介导的自身免疫反应的分子机制，为揭示SLE的发病机制及治疗提供新思路和新策略。