α-KG介导芳香烃受体AhR调节巨噬细胞极化在牙周炎症中的作用及机制

牙周炎的组织破坏主要由机体对感染的免疫应答造成，巨噬细胞M1/M2极化平衡是其中的重要环节。近年研究提示，细胞代谢影响M1/M2极化的精细调控，但确切机制尚不清楚。我们前期研究发现：牙龈卟啉单胞菌（Pg）可通过下调巨噬细胞代谢产物α-酮戊二酸（α-KG）促进M1极化、抑制M2极化。进一步测序分析显示：α-KG显著上调巨噬细胞中芳香烃受体（AhR）的表达，且AhR在炎症牙周组织中高表达。在AhR敲减巨噬细胞中，Pg感染后M1极化相关分子显著上调、M2标志分子下调。据此推测：代谢产物α-KG可能通过诱导AhR的表达、促进巨噬细胞M2极化，从而抑制牙周炎的疾病进程。为此，本项目将进一步阐明AhR通过促进巨噬细胞M2极化调控牙周炎病变的重要作用；并在分子水平解析代谢产物α-KG促进AhR表达的具体机制。本项目的实施将对深入认识牙周炎发病机制有重要意义，并可为牙周炎的预防和治疗提供新思路及理论依据。

Immune responses of host to the pathogens are implicated in periodontal tissue damage. Keeping the balance of macrophage polarization into M1/M2 is one of the important regulatory mechanisms in innate immune response. Recent researches report that cell metabolism plays a pivotal role in the delicate regulation of macrophage polarization but the exact mechanism underneath remains unclear. Our preliminary data revealed that Porphyromonas gingivalis (Pg) promoted M1 polarization and production of pro-inflammatory factors by decreasing the production of α-ketoglutarate (α-KG). Further sequencing showed that α-KG significantly upregulated the expression of aryl hydrocarbon receptor (AhR) in macrophages that is prevalent in inflamed periodontal tissues. Moreover, M1 polarization related molecules and inflammatory factors increased significantly after knock-down of AhR in macrophages. Therefore, we hypothesize that the expression of AhR on macrophages through α-KG regulation can promote M2 polarization and thus alter the development of periodontal inflammation. In this research, we underpin in vitro and in vivo the role of AhR regulated by metabolites on macrophage polarization and thus altering the pathogenesis of periodontal inflammation and further investigate the specific molecular mechanism of AhR regulation by α-KG. Through this research, we aim to deepen the current understanding of the pathogenesis of periodontal inflammation and provide basis for potential novel methods in the treatment of periodontitis.