IRF4/IRF5双向调控巨噬细胞分化在慢性排斥反应中的作用及机制研究

It is reported that macrophage subsets（M1 and M2）are involved in chronic rejection（CR）and affect the long-term outcome of allografts. Our preliminary studies as well as recent studies by other groups have shown that CD206+M2 macrophages could accelerate CR in both human renal allografts and murine cardiac grafts suffering from CR while iNOS+M1 macrophages have no effects on CR. Therefore, we speculate that the difference of infiltrating macrophages in the grafts may affect CR progress. Studies have demonstrated that interferon regulatory factor 4/5 (IRF4/IRF5) bi-directionally regulate macrophage differentiation, but its role in CR remains unknown. Therefore, this project was designed to further verify which subsets of macrophages (M1 or M2) contribute to CR in clinical renal allografts and murine cardiac and kidney grafts suffering from CR. By using IRF4/IRF5 myeloid conditional knockout mice, we aim to explore the bidirectional regulation function of IRF4/IRF5 in macrophage differentiation by bone marrow derived macrophage in vitro and LPS induced endotoxin shock model in vivo. Furthermore, we will explore its key role in regulating CR in mouse heart transplantation model. Our findings may provide new insights and strategies for clinic treatment of CR.

不同亚型巨噬细胞（M1和M2）在慢性排斥反应（chronic rejection ，CR）中均有重要作用，影响移植物长期存活。其它团队及我们前期研究表明，在临床移植肾及小鼠心脏CR模型中CD206+M2 型巨噬细胞均能加重CR，而iNOS+M1型与移植物预后无关，因此我们推测移植物浸润巨噬细胞的表型差异能影响CR进程。干扰素调节因子4/5（IRF4/IRF5）已被证实能双向调控巨噬细胞分化，但其在CR中的作用未见相关报道。本课题拟在临床肾移植CR及小鼠不同器官CR模型中，深入探讨不同亚型巨噬细胞在CR中的作用。同时，我们前期已建立IRF4/IRF5髓系特异性敲除小鼠，本课题拟利用这两种小鼠，体外在骨髓来源巨噬细胞分化体系、体内在LPS诱导内毒素休克模型中研究IRF4/IRF5对巨噬细胞分化的双向调控作用，并进一步在小鼠心脏CR模型中研究其对CR的调控作用，为临床CR治疗提供新的依据。

不同亚型巨噬细胞（M1和M2）在慢性排斥反应（chronic rejection ，CR）中均有重要作用，影响移植物长期存活。其它团队及我们前期研究表明，在小鼠心脏CR模型中CD206+M2 型巨噬细胞均能加重CR，而iNOS+M1型与移植物预后无关，因此我们推测移植物浸润巨噬细胞的表型差异能影响CR进程。干扰素调节4/5（IRF4/IRF5）已被证实能双向调控巨噬细胞分化，但其在CR中的作用未见相关报道。我们前期已建立IRF4/IRF5髓系特异性敲除小鼠，本课题利用这两种小鼠，在骨髓来源巨噬细胞分化体系中研究IRF4/IRF5对巨噬细胞分化的双向调控作用，发现IRF4条件性敲除小鼠来源骨髓巨噬细胞不易向M2型分化，作为移植受体，心脏移植物CR程度明显减轻。相反，IRF5条件性敲除小鼠来源骨髓巨噬细胞易向M2型分化,对应移植物会发生明显CR。这些结论为临床CR治疗提供新的依据和治疗靶点。