Abstract：
Transplant vasculopathy is characterized by endothelial apoptosis, which modulates the local microenvironment. Milk fat globule epidermal growth factor 8 (MFG-E8), which is released by apoptotic endothelial cells, limits tissue damage and inflammation by promoting anti-inflammatory macrophages. We aimed to study its role in transplant vasculopathy using the murine aortic allotransplantation model. BALB/c mice were transplanted with fully mismatched aortic transplants from MFG-E8 knockout (KO) or wild type (WT) C57BL/6J mice. Thereafter, mice received MFG-E8 (or vehicle) injections for 9 weeks prior to histopathological analysis of allografts for intimal proliferation (hematoxylin and eosin staining) and leukocyte infiltration assessment (immunofluorescence). Phenotypes of blood leukocytes and humoral responses were also evaluated (flow cytometry and ELISA). Mice receiving MFG-E8 KO aortas without MFG-E8 injections had the most severe intimal proliferation (p < 0.001). Administration of MFG-E8 decreased intimal proliferation, especially in mice receiving MFG-E8 KO aortas. Administration of MFG-E8 also increased the proportion of anti-inflammatory macrophages among graft-infiltrating macrophages (p = 0.003) and decreased systemic CD4+ and CD8+ T-cell activation (p < 0.001). An increase in regulatory T cells occurred in both groups of mice receiving WT aortas (p < 0.01). Thus, the analarmin MFG-E8 appears to be an important protein for reducing intimal proliferation in this murine model of transplant vasculopathy. MFG-E8 effects are associated with intra-allograft macrophage reprogramming and systemic T-cell activation dampening.
摘要：
移植血管病变的特点是内皮细胞凋亡，调节本地微环境。乳脂球表皮生长因子8（MFG-E8），由凋亡的内皮细胞释放，通过促进抗炎巨噬细胞来限制组织损伤和炎症。我们旨在使用鼠主动脉同种异体移植模型研究其在移植血管病变中的作用。用来自MFG-E8敲除(KO)或野生型(WT)C57BL/6J小鼠的完全错配的主动脉移植物移植BALB/c小鼠。此后,小鼠接受MFG-E8（或媒介物）注射9周，然后进行组织病理学分析以进行内膜增殖（苏木精和伊红染色）和白细胞浸润评估（免疫荧光）。还评估了血液白细胞的表型和体液应答(流式细胞术和ELISA)。接受MFG-E8KO主动脉而不注射MFG-E8的小鼠具有最严重的内膜增殖(p<0.001)。MFG-E8的给药减少了内膜增殖，特别是在接受MFG-E8KO主动脉的小鼠中。MFG-E8的施用还增加了移植物浸润巨噬细胞中抗炎巨噬细胞的比例(p=0.003),并降低了系统性CD4+和CD8+T细胞活化(p<0.001)。在接受WT主动脉的两组小鼠中发生调节性T细胞的增加(p<0.01)。因此，analarminMFG-E8似乎是这种小鼠移植血管病变模型中减少内膜增殖的重要蛋白.MFG-E8效应与同种异体移植物内巨噬细胞重编程和系统性T细胞活化抑制有关。
