IL-33/ST2通过Tregs介导“代谢-免疫”双向调控机制治疗肥胖诱导糖尿病的研究

调节性T细胞（Treg）的抗炎与组织修复功能是治疗肥胖相关糖尿病的重要靶点与研究热点。课题组与国外研究均证实IL-33通过Treg能有效改善胰岛素抵抗、保护β细胞，但机制有待深入阐明。我们率先发现IL-33影响Treg细胞代谢功能以及糖脂代谢通路中多种关键酶的基因表达，该现象与IL-33介导的HIF1α对抗PI3K-AKT-mTOR密切相关。据此推测，IL-33通过重塑Treg代谢格局，完成其增殖、分化及免疫抑制功能的执行，而IL-33介导代谢通路间的正负反馈平衡机制是Treg能量代谢调控的关键。本项目拟采用糖脂代谢途径抑制剂、通路干预、过继转移等，结合分子生物学、代谢组学、体内免疫调控代谢作用分析等，从整体、细胞、分子等层面系统阐明IL-33介导Treg代谢重塑的网络调控分子机制，明确IL-33介导Treg代谢重塑是IL-33改善糖脂代谢紊乱的关键环节，为肥胖诱导的糖尿病治疗提供新思路。

Regulatory T cells (Treg) are important immune cell subsets that control inflammatory reactions and promote tissue repair. They are found to maintain glucose and lipid homeostasis and become an essential target and research focus. Our previous study and international relevant studies both confirmed that IL-33 could improve insulin resistance and protect β cells through increasing the number of Treg, but the specific mechanism needs to be clarified by further research. On the basis of our previous project, we found that IL-33 promoted metabolic function of Treg, stimulated changes in the expression of gene that control metabolic process. These results were consistent with the changes of signaling pathways, including that IL-33 inhibited the expression of HIF1α and increased the expression of PI3K-AKT-mTOR. Therefore, we proposed that IL-33 manipulates the metabolic state of Treg to modify their proliferation, differentiation and suppressive function, and IL-33-mediated negative and positive feedback are the factors in the metabolic process that drive the energy metabolism regulation. In this project, we will use inhibitors interferering glucose/lipid metabolic process and signaling pathways, as well as adoptive transfer of Treg, combining molecular biotechnology and metabolomics and immune regulation of metabolism analysis, to systematically clarify the molecular regulatory network in IL-33-mediated metabolic reprogramming of Treg and elucidate their key role in ameliorating glucose-lipid metabolism disorder. This project will reveal novel strategies for treatment of obesity-induced diabetes.