IL-33促进MSC治疗心梗疗效的机制研究

Cardiovascular disease is the leading cause of human death. Acute inflammatory response happens following myocardial infarction. Heart remolding was induced by excessive inflammation is the main reason of heart failure, but it is not clear how to regulate inflammation after myocardial infarction. Interleukin 33 (IL-33), a new member of IL-1 family, participates in regulatory activity of many inflammatory cells. Mesenchymal stem/stromal cells have certain immunoregulatory function and have been used in many diseases, but how to enhance the immunoregulatory function is the current issue. We believe that enhancement of the regulatory ability of MSCs and improvement of the microenvironment of infact zone, is the key way of cura of MSCs. We observed a prior outcome that IL33-MSCs enhanced the polarization of M2 macrophage and Treg, suggested that IL33-MSCs have benign inflammatory regulating ability. This project could overexpress IL-33 in MSCs, and then detect the influence of IL33-MSCs on the differentiation of Th1/Th2/Th17/Treg and polarization of M1/M2 macrophage through flow cytometry, RNA-seq and immunofluorescence in vitro; To clear-cut the relationship of IL33-MSCs with the ability of inflammatory regulation and recovery of heart function, we will treat the infarcted heart with IL33-MSCs and detect by cardiac echocardiography testing, apoptosis of myocytes, and inflammatory relative signaling in vivo. This project could offer new theory in inflammatory regulation and heart remolding after myocardial infarction.

心血管疾病是人类健康的头号杀手，心梗后伴随剧烈炎症反应引起的心室异常重构是心力衰竭的重要原因，但如何调控心梗后炎症目前仍不清楚。白细胞介素33（IL-33）可调节多种免疫细胞活性。间充质干细胞（MSC）具有一定的免疫调节功能，在多种疾病中广泛应用，但其治疗效果有待提高。我们认为提高MSCs免疫调节能力，是MSCs治疗心梗的关键。我们前期结果表明，IL-33高表达的MSCs（IL33-MSCs）在体外可以增加M2巨噬细胞极化和Treg分化，表明其具有良好的免疫调节能力。本项目拟通过流式细胞术、免疫荧光等技术，体外研究IL33-MSCs对T细胞分化和巨噬细胞极化的影响；体内移植IL33-MSCs对心梗进行治疗，通过心脏超声、 RNA-seq和相关炎症信号通路检测等手段，明确IL33-MSCs的免疫调节功能与心功能恢复的关系。本项目的顺利实施能够为心梗后炎症调节和心室重构提供新的见解。

白细胞介素33（Interleukin-33, IL-33）是 IL-1 超家族的新成员，是一种具有多种功能的新型免疫细胞因子。本项目经过研究发现，IL-33在低氧条件下的MSCs和心肌细胞中或心梗组织中的表达显著降低。此外，我们在MSCs中高表达IL-33，MSCs的免疫调节功能显著升高，主要表现为调控巨噬细胞的极化，增加修复型巨噬细胞的比例。项目组还通过心肌内注射IL33-MSCs对心肌梗塞进行治疗，结果发现IL33-MSCs可以增加心梗组织中CD68+CD206+修复型巨噬细胞的比例，减少心梗微环境的炎症程度和心梗的纤维化程度，对心肌梗死起到治疗作用。综上，本项目阐明IL33-MSCs治疗心肌梗死的作用和机制，为心肌梗死的治疗提供新的靶点。