MSC通过TGF-β调控巨噬细胞极化在治疗SLE中的作用及机制研究

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by inflammation. Macrophages can be categorized generally as classical (M1) and nonclassical, or alternatively activated (M2) polarization. Studies suggest that M1 subtype macrophages play an important inflammatory role in SLE pathogenesis. Further, apparently reduced populations of M2 subtype macrophages may contribute to the lack of anti-inflammatory activity apparent in the disease. An imbalance of M1 over M2 may explain the runaway inflammation that is an essential feature of SLE. Our previous data showed the reduced populations of M2 subtype macrophages in SLE patients, while MSCT in the lupus-prone mouse model promotes M2 macrophage polarization. Additionally, there were elevated TGF-β levels in co-culture system between MSC and SLE macrophage, and TGF-β was reported to promote M2 macrophage polarization, suggesting that the regulatory effects of MSC on macrophage polarization might be mediated by TGF-β. Based on our previous work, in the present study, we will study the effects of MSC on SLE macrophage polarization, and explore the role and mechanism of MSC in regulating macrophage polarization via TGF-β. In addition, the cytokines and signal pathways which upregulated TGF-β expression will be analyzed. This study will uncover the role and mechanism of MSC in the treatment of SLE, which provides a theoretical basis for the clinical application of MSC.

系统性红斑狼疮（SLE）是一种全身性自身免疫疾病，在SLE中致炎型巨噬细胞（M1）大量活化，抑炎型巨噬细胞（M2）表达降低，M1/M2的失衡被认为是其发病的一个重要原因。前期用间质干细胞（MSC）移植治疗SLE特别是狼疮性肾炎取得了显著疗效，但机制尚不清楚。我们研究发现，MSC移植治疗狼疮鼠能促进巨噬细胞向M2型转化；在MSC和SLE巨噬细胞共培养后MSC释放的细胞因子TGF-β增多，而TGF-β可以刺激巨噬细胞向M2型极化。推测，MSC对SLE巨噬细胞极化的调控作用是由TGF-β所介导。在前期基础上，本项目将进一步探讨MSC对巨噬细胞极化方向的调控作用，重点探讨MSC释放TGF-β对巨噬细胞极化的调控作用及其机制，同时分析诱导MSC释放TGF-β的细胞因子及其信号通路。通过研究，阐明MSC在治疗SLE中的作用及其机制，为临床推广应用MSC治疗提供理论依据。

系统性红斑狼疮（SLE）是一种全身性自身免疫病，巨噬细胞在SLE发病机制中扮演重要角色。本项目中我们比较了SLE及正常巨噬细胞表型、免疫调节能力和吞噬功能的差异，研究发现SLE巨噬细胞CD206表达下降，抗炎细胞因子表达减少，对CD4+ T细胞增殖抑制能力降低，吞噬功能下降。间充质干细胞（mesenchymal stem cell, MSC）移植治疗取得了较好的疗效，但MSC治疗SLE的机制及其对SLE巨噬细胞的调控尚不清楚。我们的研究发现MSC可改善SLE巨噬细胞表型、免疫调节能力和吞噬功能，但对促炎-抗炎相关因子的产生影响甚微。MSC移植治疗狼疮鼠可显著改善狼疮鼠腹腔和肾脏巨噬细胞表型、免疫调节能力和吞噬功能，提示MSC对SLE巨噬细胞的调控有可能是MSC发挥治疗作用的一个重要机制。进一步体外研究发现MSC可通过分泌IL-6调控SLE巨噬细胞表型和吞噬功能，阐明了MSC调控巨噬细胞的机制。本项目研究结果提示，MSC可能通过调控巨噬细胞发挥疗效，为临床推广应用MSC治疗SLE提供理论依据。