重组IL-37基于IL-6/Stat3信号通路调节Th17/Treg平衡治疗病毒性心肌炎的机制研究

Th17/Treg ratio imbalance plays an important role in the pathogenesis of Viral Myocarditis(VMC).IL-6/STAT3 signaling pathway can induce the differentiation of T cells into Th17.IL-37 is an anti-inflammatory factor that can inhibit the inflammatory cytokine release especially IL-6. Our previous studies demonstrated that IL-37 can inhibit the activity of Th17 cells and improve the condition of VMC, but the mechanism is unknown. In our study, we will construct, express and purify recombinant human IL-37, analyze its effect on activated Th17 cells in vitro, and explore the pathway and mechanism of inhibiting Th17 cell activation; treat acute and chronic VMC mice with recombinant human IL-37. Pathological Changes of myocardial, cardiac function, Th17/Treg cell ratio, transcription factors and cytokines of Th17/Treg cells, activation of IL-6/STAT3 pathway will be evaluted to confirmed that recombinant human IL-37 can improve VMC mice through IL-6/STAT3 signaling pathway by reconstructing Th17/Treg balance. The results of this study can further clarify the mechanism of IL-37 in VMC and provide experimental evidence for the treatment of VMC.

Th17/Treg细胞失衡在病毒性心肌炎（VMC）自身免疫损伤过程中发挥着重要作用，IL-6/STAT3通路的活化可以使初始T细胞向Th17细胞方向分化。我们前期研究证实IL-37可以抑制Th17细胞活性并改善VMC病情，但机制不明。本课拟构建、表达并纯化重组人IL-37，体外分析其对Th17和Treg细胞活性的影响，探讨其抑制Th17细胞活化的通路和机理；应用重组人IL-37干预急慢性VMC小鼠，从VMC病情、心脏功能、心肌病理、Th17/Treg细胞比例、Th17和Treg细胞转录因子及细胞因子、IL-6/STAT3通路活化程度的变化，证实重组人IL-37可通过IL-6/STAT3通路改善VMC小鼠Th17/Treg失衡状态减缓炎症病变，避免心肌纤维化。该研究可进一步阐明IL-6/STAT3通路在VMC发生发展中的作用及IL-37治疗VMC的作用机制。

Th17/Treg细胞失衡在病毒性心肌炎（VMC）自身免疫损伤过程中发挥着重要作用，IL-6/STAT3通路的活化可以使初始T细胞向Th17细胞方向分化。我们前期研究证实IL-37可以抑制Th17细胞活性并改善VMC病情，但机制不明。本研究通过构建、表达并纯化重组人IL-37，体外研究其对Th17和Treg细胞活性的影响，并探索其抑制Th17细胞活化的通路和机理；同时，我们使用重组人IL-37来干预患有急性和慢性VMC的小鼠。我们通过各个方面（VMC病情、心脏功能、心肌病理改变、Th17/Treg细胞比例、Th17和Treg细胞转录因子及细胞因子、IL-6/STAT3通路活化程度的变化）来证实人IL-37改善VMC小鼠心脏炎症相关病变和心肌纤维化。本课题的机制研究进一步阐明：1. IL-37通过调控Caspases, Bcl/Bax和p38MAPK信号通道从而显著减轻CVB3导致的心肌细胞凋亡。 2. IL-37通过减少IL-37-IL-1R8-IL-18RA复合体的形成从而抑制NF-κB 信号途径和NLRP3炎症小体从而减轻心肌组织内的炎症反应。因而，IL-37通过降低心肌细胞凋亡和减轻局部炎症反应强度来起到治疗VMC的作用。