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

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.

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。

肥胖加重牙周炎的机制仍不清楚，免疫反应异常可能是关键，其常受到代谢编程的调控。本项目以精氨酸代谢为切入点，探索了肥胖与牙周炎的代谢免疫学联系。首先，我们完善了超重、肥胖与牙周炎的复合模型的建立方法，提出了复合模型建立面临的特殊问题，并给出了一些对策。利用该模型发现，肥胖小鼠应对牙周炎的异常免疫反应可形成于超重阶段，提示肥胖个体的牙周炎易感性应该提早防治。而且，我们首次描述了肥胖动物应对牙周炎的牙周组织代谢组学变化，发现其代谢反应广度和强度均高于正常体重对照。该发现初步奠定了肥胖个体易感于牙周炎的代谢基础，并筛选出多个相关代谢通路和代谢物。最后，我们首次探索了肥胖动物应对牙周炎的牙周组织精氨酸代谢变化，发现肥胖加速精氨酸的分解代谢，并使其下游产物向M2巨噬细胞相关代谢物偏转。该发现从代谢层面解释了肥胖个体应对牙周炎的巨噬细胞异常表型的分子机制，并提示精氨酸代谢干预有望成为肥胖与牙周炎共患者的潜在治疗策略。