TSLP在急性心肌梗死后Tγδ17细胞反应中的作用和机制研究

Our previous study confirmed that Tγδ17 cell response aggravated adverse ventricular remodeling after acute myocardial infarction (AMI). Thymic stromal lymphopoietin (TSLP) play a regulator role in the inflammatory responses. Our preliminary experiments found that the myocardial expression of TSLP increased after AMI and TSLP may aggravated adverse ventricular remodeling by regulating Tγδ17 cell response. However, the exact relationship between the two deserves further studies. The project plans to ① observe the expression and cellular localization of NF-κB and TSLP in vivo, and investigate the regulatory effect of NF-κB on TSLP expression in vitro, to clarify the upstream regulatory mechanism of TSLP after AMI; ② observe the effect of blocking TSLP or increasing TSLP on ventricular remodeling and Tγδ17 cell response, and the effect of removing γδT cell on TSLP’ activity on ventricular remodeling, to clarify whether TSLP promotes adverse ventricular remodeling by regulating Tγδ17 cell response; ③ clarify whether TSLP indirectly acts through dendritic cells and/or directly acts on Tγδ17 cell response to aggravate adverse ventricular remodeling. The project helps to reveal the relationship between TSLP and the inflammatory response after AMI and improve immune theory for ventricular remodeling, providing a new target for intervention.

我们的前期研究证实，Tγδ17细胞反应促进急性心肌梗死（AMI）后不良心室重塑。胸腺基质淋巴细胞生成素（TSLP）在炎症反应中常扮演“策划者”的角色。我们的预实验发现，TSLP在AMI后表达升高和促进不良心室重塑，其作用可能与Tγδ17细胞反应有关，但二者的确切关系和调控机制有待进一步阐明。本项目拟①观察AMI后NF-κB和TSLP的表达及细胞定位，明确NF-κB对TSLP的表达调控，阐明AMI后TSLP的上游调控机制；②观察阻断TSLP或升高TSLP后对AMI后心室重塑的和Tγδ17细胞反应影响，以及去除γδT细胞对TSLP作用的影响，阐明TSLP是否通过调控Tγδ17细胞反应促进不良心室重塑；③从间接通过树突状细胞作用和/或直接作用两个角度阐明TSLP调控AMI后Tγδ17细胞反应的机制。结果有助于揭示TSLP与AMI后免疫炎症的关系，完善AMI后炎症反应理论，为其干预提供新的靶点。

急性心肌梗死严重危害人类健康。由于冠心病治疗学的长足进展，心肌梗死后的急性期存活率明显改善，但梗死后慢性心力衰竭的发病率和死亡率却逐年上升。心室重塑是慢性心力衰竭的病理生理基础。近年来的研究证实，炎症反应在AMI后心室重塑过程中起到重要作用。既往研究表明，TSLP在皮肤炎症，气道炎症，肠道炎症的相关疾病及肿瘤免疫中均具有重要的作用。然而，TSLP与AMI后心脏局部炎症反应的关系尚未见相关报道。我们发现，TSLP在梗死后的心脏局部表达水平显著增高，且呈现动态变化。TSLPR表达于梗死心脏中浸润的多种免疫细胞，包括T细胞，单核/巨噬细胞，树突状细胞。敲除TSLP受体后，心肌梗死模型小鼠的心功能恶化，不良心室重塑加剧。TSLP通过调节心脏局部的Treg/Th17平衡抑制不良心室重塑。我们的研究一方面丰富了心肌梗死后心室重塑的机制研究内容，另一方面为其干预提供新的干预靶点。