心肌炎是以单核/Mφ浸润、进行性心肌损伤为特征的炎性疾病。预实验发现EAM小鼠心肌细胞释放的Reg3β可诱导Mφ向组织修复型转变，而Mφ分泌的N2-HMGB1可促进心肌细胞去分化。因此推论：EAM时去分化心肌细胞释放Reg3β调控浸润Mφ再编程；后者分泌N2-HMGB1促进心肌细胞去分化和增殖，进一步释放Reg3β，形成正反馈环路，参与损伤心肌修复。本课题拟从三方面验证上述假说：①体外阐明Reg3β调控心肌浸润Mφ再编程及分泌N2-HMGB1的分子机制；②体外阐明N2-HMGB1调控心肌细胞去分化、增殖及Reg3β释放的机制；③体内利用Reg3β-/-、HMGB1-/-、单核/Mφ-/-小鼠等，证实Reg3β/N2-HMGB1环路调控Mφ再编程参与EAM小鼠受损心肌修复的作用。课题研究结果将揭示心肌局部微环境对Mφ再编程及心肌修复的调控机制，为心肌炎的干预治疗提供新的思路和靶点。

Myocarditis is an inflammatoy disease charaterized by monocytes/macrophages infiltration and progressive myocardial injury. Our preliminay data showed that, in experimental autoimmune myocarditis (EAM) mice, Reg3β released by cardiomyocytes could promote the reprogramming of macrophages into tissue repaire type, and N2-HMGB1 secreted by macrophages could promote the dedifferentiation of cardiomyocytes. Therefore, we hypothesize that dedifferentiated cardiomyocytes of EAM mice regulate the reprogramming of infiltrating macrophages by releasing Reg3β; and then reprogammed macrophages promote the dedifferentiation and proliferation of cardiomyocytes and the further release of Reg3β by secreting N2-HMGB1; Reg3β and N2-HMGB1 form a positive feedback regulation loop contribute to the repair of injured myocardium. We intend to verify above hypothesis from three aspects: ①In vitro, to clarify the molecular mechanism of Reg3β regulating marophage reprogramming and N2-HMGB1 secreting; ②In vitro, to clarify the molecular mechanism of N2-HMGB1 regulating the dedifferentiation and proliferation of cardiomyocytes and Reg3β releasing; ③In vivo, to confirm the role of Reg3β/N2-HMGB1 loop regulating macrophage reprogramming involved in the repair of injured myocardial tissue in EAM by the application of Reg3β-/-, HMGB-/-, and monocytes/microphages-/-mice. Following the project, we will expect to reveal the regulating mechanism of myocardial microenviroment on macrophage reprogramming and cardiac repair, and provide new ideas and targets for the intervention therapy of myocarditis.