巨噬细胞精氨酸代谢失稳介导肥胖相关牙周组织破坏的代谢免疫学机制

肥胖加重牙周炎的生物学机制亟待阐明，巨噬细胞（Mφ）反应异常可能是核心机制。最新研究表明，Mφ免疫功能受代谢途径的广泛调节。我们前期发现，牙周炎时，牙周组织Mφ的M1（促炎）、M2（抗炎）型功能及相关的精氨酸代谢酶NOS2-Arg1平衡轴两端均被激活，且存在M1/NOS2向极化。而且，肥胖机体应对牙周感染时，牙周组织和系统的Mφ炎症反应低弱（包括M1/NOS2），而Arg1表达亢进。然而，Mφ精氨酸代谢在肥胖与牙周炎交织中的作用及调控机制仍不清楚。本项目从代谢免疫学的新视角，以NOS2/Arg1及上游低氧代谢相关的HIF-1/2α为纵深线，探索精氨酸代谢失稳介导的Mφ表型异常在肥胖加重牙周组织破坏中的作用及调控机制，为代谢性-感染性炎症的交织提供新的生物学解释及代谢免疫干预靶点。

The biological mechanisms by which obesity promotes periodontitis are poorly understood, and impaired macrophage (Mφ) response might be a key player. Emerging studies suggests intense controls of immune functions in Mφ by metabolic processes, in which nitric oxide synthase 2 (NOS2)-arginase 1 (Arg1) balance and its controlling arginine metabolism are at the regulation center of Mφ phenotype. We team recently found that both the pro-inflammatory M1 and anti-inflammatory M2 functions and the corresponding activities of NOS2-Arg1 balance on both sides were enhanced, with an M1/NOS2 polarization. Moreover, in the context of obesity, Mφ showed blunted inflammatory response (including decreased NOS2/M1 function) but enhanced Arg1 levels. However, the role of arginine metabolism in Mφ and how it is modulated in the correlation between obesity and periodontitis are largely unknown. From the new perspectives of immunometablism, this project aims to explore the role of dysregulated arginine metabolism, which impairs Mφ phenotypes, and its modulating mechanisms by which obesity promotes periodontal destruction, to deepen into NOS2/Arg1 and upstream hypoxia-related HIF-1/2α (i.e., HIF-1/2α- NOS2/Arg1 axis) and to provide new biological plausibility that links the metabolic and infectious inflammation and more potent interventional targets.