GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency.
GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency.
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DOI：
10.1172/jci67356
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
P. Ye;Wenhao Chen;Jie Wu;Xiaofan Huang;Jun Li;Sihua Wang;Zheng Liu;Guo-hua Wang;X. Yang-X.
中科院分区：
文献类型：
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作者：
P. Ye;Wenhao Chen;Jie Wu;Xiaofan Huang;Jun Li;Sihua Wang;Zheng Liu;Guo-hua Wang;X. Yang-X.
杂合性功能丧失SMAD3(母亲抗十足瘫痪同源基因3)突变会导致动脉瘤-骨关节炎综合征(AOS)。在目前的研究中，我们发现缺乏Smad3的小鼠具有类似于AOS的血管表型，以动脉瘤的进行性发展为标志。这些动脉瘤与各种病理改变有关，表现为跨壁的炎性细胞浸润。来自Smad3-/-小鼠的骨髓移植在受照射的WT受体小鼠中引起了主动脉炎和主动脉根部扩张。移植Smad3-/-小鼠的CD4+T细胞也会导致Smad3+/+受体小鼠的主动脉炎，而Smad3-/-小鼠的CD4+T细胞的耗尽则减少了主动脉根部的炎性细胞的渗透。此外，在Smad3+/-小鼠中，干扰素-γ缺乏增加，而IL-17缺乏减少，病情加重。用细胞因子定量体阵列法检测细胞因子的分泌，发现Smad3-/-CD4+T细胞比Smad3+/+CD4+T细胞分泌更多的GM-CSF。GM-CSF可诱导CD11b+Gr-1+Ly-6CHI炎性单核细胞在主动脉根部聚集，而Smad3-/-小鼠应用抗GM-CSF单抗后，主动脉根部炎症和扩张明显减轻。我们还在一个胸主动脉瘤家族中发现了错义突变(c.985A>；G)。在这些患者的主动脉标本中观察到强烈的炎性浸润和GM-CSF的表达，提示GM-CSF可能参与了AOS的发生发展。
Heterozygous loss-of-function SMAD3 (Mothers against decapentaplegic homolog 3) mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3 had a vascular phenotype similar to AOS, marked by the progressive development of aneurysms. These aneurysms were associated with various pathological changes in transmural inflammatory cell infiltration. Bone marrow transplants from Smad3-/- mice induced aortitis and aortic root dilation in irradiated WT recipient mice. Transplantation of CD4+ T cells from Smad3-/- mice also induced aortitis in Smad3+/+ recipient mice, while depletion of CD4+ T cells in Smad3-/- mice reduced the infiltration of inflammatory cells in the aortic root. Furthermore, IFN-γ deficiency increased, while IL-17 deficiency decreased, disease severity in Smad3+/- mice. Cytokine secretion was measured using a cytokine quantibody array, and Smad3-/- CD4+ T cells secreted more GM-CSF than Smad3+/+ CD4+ T cells. GM-CSF induced CD11b+Gr-1+Ly-6Chi inflammatory monocyte accumulation in the aortic root, but administration of anti-GM-CSF mAb to Smad3-/- mice resulted in significantly less inflammation and dilation in the aortic root. We also identified a missense mutation (c.985A>G) in a family of thoracic aortic aneurysms. Intense inflammatory infiltration and GM-CSF expression was observed in aortas specimens of these patients, suggesting that GM-CSF is potentially involved in the development of AOS.