调节性B细胞在AMI后心室重塑中的作用和机制研究

Recent studies show that lymphocyte-mediated inflammation is closely related to ventricular remodeling after acute myocardial infarction (AMI). Regulatory B cells (Breg) is a subset of B cells with immunomodulatory function. Our previous study found that Breg infiltrated the myocardium after AMI and adoptive transfer of Breg markedly attenuated ventricular remodeling and improved cardiac function after AMI. Therefore, we believe that Breg is protective in AMI and the detailed mechanism of its regulation needs to be elucidated. The project plans to: ① observe the expression and unique phenotype of Breg after AMI; ②observe the effects of Breg replenishment or depletion on ventricular remodeling after AMI through adoptive transfer of Breg or B cell-specific knockout of IL-10 mice; ③observe the effects of Breg replenishment or depletion on monocyte, macrophage and Treg after AMI, and the effects of blocking IL-10，TGF-β1 or IL-35 on the above process, to investigate the target cells and functional mediators of Breg regulation on ventricular remodeling after AMI. These exploratory studies will lead to a comprehensive understanding of the role of Breg in ventricular remodeling after AMI, and provide the theoretical and experimental basis for the development of targeted therapy in ventricular remodeling after AMI.

近年来的研究表明急性心肌梗死（AMI）后的心室重塑与淋巴细胞介导的免疫炎症关系密切。调节性B细胞（Breg）是具有免疫调节作用的B细胞亚群。我们的前期研究发现AMI后Breg浸润到心肌组织，过继转输Breg明显减轻AMI后的心室重塑并改善心功能。因此我们认为Breg在AMI后心室重塑中具有保护作用，其具体调控机制有待进一步阐明。本项目拟：①观察AMI后Breg的表达规律和独特表型；②应用Breg过继转输或B细胞特异性敲除IL-10小鼠观察增加或去除Breg对AMI后心室重塑的影响；③观察增加或去除Breg对AMI后单核细胞，巨噬细胞和Treg的影响，在上述过程阻断IL-10，TGF-β1或IL-35，明确Breg调控AMI后心室重塑的靶细胞和效应分子。最终全面深入地阐明Breg在AMI后心室重塑中的保护作用和机制，为AMI后心室重塑的靶向治疗提供新的理论基础和实验依据。

过度激活的炎症反应会导致心肌梗死（MI）后的不良心室重构，调节性B细胞（Breg）是一个新发现的B细胞亚群，在许多免疫和炎症相关疾病中具有免疫调节作用。我们的研究旨在明确Breg细胞是否对MI后的心室重构具有保护作用，并探讨其机制。研究显示，MI后Breg细胞在心脏中聚集，过继转输Breg细胞能够减轻小鼠MI后的心室重构，表现为心功能改善、心脏梗死面积减小以及纤维化程度减轻，而对生存率没有影响。进一步研究发现，过继转输Breg细胞减少了Ly6Chi单核细胞向梗死心脏的浸润，而对Ly6Clo单核细胞、T细胞和中性粒细胞没有影响。机制研究发现，Breg细胞降低了单核细胞上趋化因子受体CCR2的表达，从而抑制了骨髓中单核细胞的动员以及从外周血向心脏的浸润。Anti-IL-10抗体阻断了Breg细胞介导的对MI的保护作用，并且逆转了Breg细胞对单核细胞迁移和CCR2表达的影响。以上研究表明，Breg细胞通过降低CCR2的表达影响单核细胞募集和动员，从而改善MI后的心室重塑。