B10调控成纤维细胞HA合成延缓EAM小鼠心肌纤维化进程的机制研究

心肌纤维化与成纤维细胞活化、Mφ再编程以及心肌细胞坏死等多因素相关，是EAM后期心肌功能不可逆转的核心事件。阐明影响纤维化发生的因素对于积极开展心血管疾病的防治具有重要意义。预实验发现EAM小鼠，脾脏B10比例增加、浸润心肌；体外B10能够抑制成纤维细胞活化、促进其HA合成；HA与Mφ的再编程以及心肌细胞的存活密切相关；而成纤维细胞能够促进B10扩增。由此提出：“B10通过抑制成纤维细胞活化、促进其HA的合成，延缓了EAM小鼠纤维化进程”的假说。为证实以上假说，课题拟从体内外两方面进行：体外阐明B10抑制成纤维细胞活化，促进其HA合成、调控心肌浸润Mφ再编程以及心肌细胞增殖的机制；体内通过使用WT、IL-10-/-、FSP1-has-/-BALB/c小鼠以及中和抗体进一步明确B10细胞在EAM小鼠心肌功能重构过程中的调控作用；为全面认识B10在炎症疾病发生及转归过程中的作用积累实验数据。

Cardiac fibrosis is a critical process of cardiac function remodeling at the last stage of experimental autoimmune myocarditis (EAM); associated with fibroblasts activation, macrophage reprogramming and apoptosis of cardiac myocytes. It is of great significance to clarify the factors of fibrosis in the prevention and treatment of cardiovascular disease. Our date showed that the proportion of B10 was up-regulated in spleen of EAM mice. Meanwhile, B10 cell was infiltrated in heart tissue. It is noted that B10 cells modulated hyaluronan (HA) synthesis in cardiac fibroblasts and inhibited cardiac fibroblasts activation; furthermore, HA contributed to macrophage reprogramming and promoted cardiac myocytes proliferation; additionally fibroblast could promote B10 expansion. Therefore, we hypothesized that "B10 cell is involved in the regulation of HA synthesis in fibroblasts, inhibited it's activation and retarded EAM mice development." To confirm the hypothesis, the project will be carried out: in vitro, to clarify the mechanisms: (1) B10 modulated HA synthesis and inhibited cardiac fibroblasts activation; (2) HA contributed to macrophage reprogramming; (3) HA promoted cardiac myocytes proliferation; in vivo, wild type, IL-10-/-, FSP1-has-/-BALB/c and neutralizing antibody will be employed to clarify B10 cells roles in myocardial function remodeling following EAM. All the data will help us to comprehensive understanding of B10 cells roles in inflammatory diseases development and resolution.