Let-7调控IL-6对SLE骨髓MSCs免疫调节DCs功能的影响及机制研究

Bone marrow derived mesenchymal stem cells (MSCs) from patients with systemic lupus erythematosus (SLE) exhibited functionally abnormalities, which might be involved in disease onset, allogeneic MSCs transplantation had therapeutic effects on lupus mice and patients, but the mechanisms are not clear yet. The expression imbalance of microRNAs (miRNAs) could cause cell dysfunction, which participates in a variety of diseases development, thus the role of miRNAs in MSCs of SLE patients need further investigation. Interleukin (IL)-6 is an important pro-inflammatory factor secreted by MSCs that could promote dendritic cells (DCs) development and activation. Production of IL-6 might be modulated by NF-κB-Lin28-Let-7-IL-6 positive feedback loop. Our previous experiments found that SLE MSCs could not efficiently inhibit DCs activation; the IL-6 was significantly higher in SLE MSCs compared to healthy controls, while expressions of let-7a and let-7f were markedly down-regulated in SLE MSCs. This project aims to further investigate whether let-7 family play a role in immune regulatory function of MSCs on DCs by modulating IL-6 expression and the underlying mechanisms, and to clarify the relationship of abnormalities of this process with SLE MSCs dysfunction for understanding SLE pathogenesis and finding out potential target. This study may provide new evidence for allogeneic MSCs transplantation in the treatment of SLE.

本课题组前期研究发现系统性红斑狼疮（SLE）患者骨髓间充质干细胞（MSCs）存在功能异常，参与其发病，异基因MSCs移植治疗SLE疗效显著，但机制尚不明确。MicroRNAs（miRNAs）表达失调可致细胞功能异常，从而参与SLE发病。白介素-6（IL-6）为MSCs分泌的重要多效性前炎症细胞因子，可维持树突状细胞（DCs）发育及活化等平衡，其产生受多因素调节，如NF-κB-Lin28-Let-7-IL-6 阳性反馈环等。我们前期发现SLE MSCs不能有效抑制DCs活化，其合成及分泌IL-6增多，而其let-7a及let-7f表达明显下调。本项目拟探讨let-7能否通过靶向IL-6影响MSCs免疫调节DCs及其机制，弄清SLE MSCs免疫调节DCs异常是否与其let-7表达及功能失调相关，深入认识SLE发病机制，寻求更有效的疾病干预靶点，为临床异基因MSCs移植治疗SLE提供理论依据。

本课题组通过体外研究发现，SLE患者骨髓MSCs中let-7f低表达可影响其增殖及凋亡功能，并可损伤其MSCs免疫调节功能，具体表现在使其不能有效上调Treg百分率，亦不能明显下调Th17百分率；而提高let-7f在MSCs中表达水平可有效逆转该过程。进一步研究表明，let-7f能够直接靶向IL-6调控STAT3信号通路发挥其对SLE MSCs功能的影响，这提示SLE MSCs功能异常可能与这一过程失调密切相关，为深入认识SLE发病机制，寻求更有效的疾病干预新靶点，并临床推广应用异基因MSCT治疗SLE提供全新思路和实验依据。