MSCs通过IL-6增强Mφ免疫调节功能在SLE治疗中的作用及机制

Systemic lupus erythematosus (SLE) is a classical inflammatory autoimmune disease. Allogeneic mesenchymal stem cells (MSCs) have been confirmed to exert therapeutic effects on SLE. Recent studies have shown that macrophages (Mφ) can reprogram their responses toward immunogenic or tolerogenic phenotypes depending on the type of environments they encountered, in the phenomenon termed “trained immunity and tolerance”. Moreover, the imbalance of immune tolerance contributes to the pathogenesis of SLE. Our previous data showed that some cytokines, related to immune tolerance, were decreased in SLE Mφ. SLE Mφ were incapable of suppressing the proliferation of CD4+ T cells effectively, which were corrected by co-cultured with MSCs. Additionally, IL-6 levels of MSCs were provoked by SLE Mφ. Based on our previous work, we speculate that MSCs alleviated SLE through promoting the immunomodulatory capacity of Mφ in an IL-6 dependent manner. In this study, we will seek to determine the immunomodulatory capacity of SLE Mφ. Importantly, we will investigate whether MSCs could influence this function of SLE Mφ, and if so, to elucidate the underlying mechanisms. This study may provide a novel theoretical basis for the clinical application of MSCs in SLE treatment.

系统性红斑狼疮（SLE）是经典的自身免疫病原型疾病，异基因间充质干细胞（MSCs）移植治疗SLE临床缓解率高，副作用少，但具体机制尚不明确。近年研究证实，巨噬细胞（Mφ）与不同环境作用后，可改变自身功能，参与免疫防御或免疫耐受，而免疫耐受失衡是SLE发病的重要机制。前期研究发现，SLE患者Mφ相关免疫调节因子显著降低，无法有效抑制T细胞过度增殖；MSCs可逆转SLE患者Mφ对T细胞增殖的抑制能力；SLE患者Mφ显著上调MSCs的IL-6水平。因此我们推测，MSCs可通过调控Mφ免疫调节功能治疗SLE，且这一过程由IL-6介导。本课题拟进一步通过体内外实验探讨SLE Mφ的免疫调节功能，明确介导MSCs调控SLE Mφ免疫调节功能的关键分子，解析Mφ在SLE发病及MSCs治疗SLE中的意义，为MSCs有效治疗SLE提供新的理论基础。

间充质干细胞移植治疗SLE患者疗效满意，但具体机制不清。CD206为抗炎巨噬细胞M2的重要表面标记，本课题研究发现，与健康者对比，SLE患者外周血巨噬细胞CD206表达水平明显下降，且患者外周血来源巨噬细胞吞噬功能明显下降。通过体外SLE患者巨噬细胞与脐带来源MSC共培养，发现MSC能显著促进SLE患者外周血来源巨噬细胞CD206表达，增强巨噬细胞对凋亡中性粒细胞及荧光微球的吞噬功能。通过MSC移植治疗狼疮鼠动物模型，发现MSC可以显著增强狼疮鼠腹腔及肾脏巨噬细胞的吞噬功能。该研究结果提示脐带MSC可能通过增强巨噬细胞表达CD206及其吞噬功能有效治疗SLE患者。