IL (Interleukin)-33 Suppresses Abdominal Aortic Aneurysm by Enhancing Regulatory T-Cell Expansion and Activity
IL (Interleukin)-33 Suppresses Abdominal Aortic Aneurysm by Enhancing Regulatory T-Cell Expansion and Activity
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IL（白细胞介素）-33 通过增强调节性 T 细胞扩增和活性来抑制腹主动脉瘤
DOI：
10.1161/atvbaha.118.312023
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发表时间：
2019-03-01
影响因子：
8.7
通讯作者：
Cheng, Xiang
中科院分区：
文献类型：
--
作者：
Li, Jingyong;Xia, Ni;Cheng, Xiang
目的 腹主动脉瘤 (AAA) 进展过程中会发生炎症。 IL（白细胞介素）-33 是一种具有多种免疫调节作用的多效细胞因子，但其在 AAA 中的作用仍不清楚。方法和结果免疫印迹、免疫组织化学和免疫荧光染色显示小鼠 AAA 病变的外膜成纤维细胞中 IL-33 表达增加。每日腹膜内施用重组 IL-33 或转基因 IL-33 表达可改善小鼠主动脉周围 CaPO4 损伤和主动脉弹性蛋白酶暴露诱导的 AAA，如主动脉扩张减弱、主动脉壁弹性碎片减少、AAA 病变胶原沉积增强、T 细胞和巨噬细胞浸润减弱、炎性细胞因子产生减少、M2 巨噬细胞极化倾斜和病变减少所证明MMP（基质金属蛋白酶）表达和细胞凋亡。流式细胞术分析、免疫染色和免疫印迹分析表明，外源性IL-33增加了主动脉周围CaPO4治疗小鼠的脾脏、血液和主动脉中的CD4(+)Foxp3(+)调节性T细胞。然而，ST2 缺陷使这些 IL-33 活性减弱。 IL-33治疗小鼠的调节性T细胞在抑制平滑肌细胞炎症细胞因子和趋化因子表达、巨噬细胞MMP表达以及增加M2巨噬细胞极化方面也表现出比载体治疗小鼠的调节性T细胞更强的活性。相比之下，IL-33 未能预防 AAA，并且在选择性耗尽调节性 T 细胞后，在 CaPO4 治疗的小鼠中失去了其有益活性。 结论 总之，这项研究通过增强 ST2 依赖性主动脉和全身调节性 T 细胞扩张及其免疫抑制活性，确定了 IL-33 在保护小鼠免受 AAA 形成中的作用。
Objective Inflammation occurs during the progression of abdominal aortic aneurysm (AAA). IL (interleukin)-33 is a pleiotropic cytokine with multiple immunomodulatory effects, yet its role in AAA remains unknown.Approach and Results Immunoblot, immunohistochemistry, and immunofluorescent staining revealed increased IL-33 expression in adventitia fibroblasts from mouse AAA lesions. Daily intraperitoneal administration of recombinant IL-33 or transgenic IL-33 expression ameliorated periaorta CaPO4 injury- and aortic elastase exposure-induced AAA in mice, as demonstrated by blunted aortic expansion, reduced aortic wall elastica fragmentation, enhanced AAA lesion collagen deposition, attenuated T-cell and macrophage infiltration, reduced inflammatory cytokine production, skewed M2 macrophage polarization, and reduced lesion MMP (matrix metalloproteinase) expression and cell apoptosis. Flow cytometry analysis, immunostaining, and immunoblot analysis showed that exogenous IL-33 increased CD4(+)Foxp3(+) regulatory T cells in spleens, blood, and aortas in periaorta CaPO4-treated mice. Yet, ST2 deficiency muted these IL-33 activities. Regulatory T cells from IL-33-treated mice also showed significantly stronger activities in suppressing smooth muscle cell inflammatory cytokine and chemokine expression, macrophage MMP expression, and in increasing M2 macrophage polarization than those from vehicle-treated mice. In contrast, IL-33 failed to prevent AAA and lost its beneficial activities in CaPO4-treated mice after selective depletion of regulatory T cells.Conclusions Together, this study established a role of IL-33 in protecting mice from AAA formation by enhancing ST2-dependent aortic and systemic regulatory T-cell expansion and their immunosuppressive activities.