Tγδ22/IL-22/Smad2 轴调控巨噬细胞分化改善心梗后心室重塑的机制研究

M2 macrophages promote the development of ventricular remodeling after myocardial infraction (MI). Tγδ22 cells regulate inflammation via secreting IL-22. Researches have shown that IL-22 can inhibit fibrosis. While the effect of IL-22 in the process of ventricular remodeling after MI remains unclear. Our previous study revealed that patients with post-MI had a higher leves of IL-22 in serum. And IL-22 levels were positively correlated with LVEF and LVFS, whereas negatively correlated with LVEDD. Besides，our preliminary experiments indicate that recombinant mouse IL-22 protein attenuates ventricular remodeling after MI . However，the role of IL-22 in MI has yet to be clarified and reported. Accordingly，We hypothesized that Tγδ22 cells are actevated and release IL-22 after MI. IL-22 unites with IL-22 receptor1, and inhibits the phosphorylation of Smad2, then reduces the differentiation of M2 macrophages, inhibits activation of TGF-β/Smad2 signal pathway, and finally decreases the myocardial interstitial fibrosis and attenuates ventricular remodeling. Our study will ensure the effect of IL-22 in ventricular remodeling post-MI, detailedly detect the mechanism of IL-22 attenuates myocardial interstitial fibrosis, and conform the pathway and target cells that IL-22 acts with by the levels of gene, molecule, cell, tissue and animal. The research firstly illustrates ventricular remodeling post-MI from the perspective of IL-22 regulating macrophages differentiation through conbining vitro test with IL-22-/-, Smad2 overexpressed virus transfection and IL-22, Anti-IL-22R1Ab intraperitoneal injection mice MI model. The results will further verify the mechanism of ventricular remodeling and provide the theoretical basis for effect target of prevention and therapy.

M2型巨噬细胞促进心梗后心室重塑的发生发展。Tγδ22通过分泌 IL-22调控组织的炎症反应。研究表明IL-22有抑制纤维化的作用，然而其在心肌梗死后心室重塑中的作用尚不清楚。前期研究发现，IL-22在心梗患者外周血中活性显著升高，且与LVEF、LVFS正相关，与LVEDD负相关。预实验表明，重组小鼠IL-22可显著改善小鼠心梗后心室重构，但其作用机制仍未阐明，且目前尚未有IL-22在心肌梗死相关区域的研究。据此我们提出Tγδ22/IL-22/Smad2 轴调控巨噬细胞分化，降低心肌间质纤维化，改善心室重塑的假说。本课题从分子、细胞、组织及动物水平等多层次明确了IL-22在心梗后心室重塑中的作用，探讨了IL-22抑制心肌纤维化的机制，确定了IL-22作用的靶细胞及通路。本实验首次从IL-22调控巨噬细胞分化这一新视点探讨心梗后心室重塑的发生发展机制，为治疗心梗后心室重塑提供实验依据及新靶点

急性心肌梗死后的心室重塑是临床上常见的进行性发展的病理生理过程，指心肌梗死后心室大小、形态、结构和功能的变化过程。本课题组前期的临床观察发现，心梗患者外周血IL-22 水平在心肌梗死后2小时、14天及28 天呈现上升趋势，各时点值均高于正常对照组，且相关性分析表明IL-22 含量与左室射血分数、左室短轴缩短率成正相关，与左室舒张末期内径成负相关.本研究通过构建前降支结扎的小鼠心梗模型，使用C57BL/6N背景的IL-22基因敲除小鼠、rmIL-22和抗小鼠IL-22R1 单克隆抗体腹腔注射等干预措施，结合体外实验阐明IL-22在心肌梗死后心室重塑进程中的作用及具体机制。结果如下：1）IL-22可能通过调节巨噬细胞极化在心肌梗死（AMI）中抑制心室重构从而发挥保护作用。2）IL-22KO可减轻阿霉素（DOX）诱导的氧化应激和心脏损伤，提示降低IL-22表达可能对化疗患者心脏有益。本实验首次从IL-22调控巨噬细胞分化这一新视点探讨心梗后心室重塑的发生发展机制，为治疗心梗后心室重塑提供实验依据及新靶点