Lou Jingyang, Zhang Bo, Cai Jingyi, Zhang Linli, Zhao Yifan, Zhao Zhihe
State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Int Immunopharmacol. 2025 Feb 6;147:113896. doi: 10.1016/j.intimp.2024.113896. Epub 2024 Dec 30.
Tissue-resident fibroblasts with immunomodulatory properties have recently been identified as key players in inflammation. However, their roles within the periodontal niche in diabetes-associated periodontitis remain unclear. Interleukin (IL)-33, known as an "alarmin" in inflammatory responses, has recently emerged as a potential contributor to periodontitis. Herein, we show that IL-33 levels are reduced in periodontal ligament fibroblasts (PDLFs) in the in vivo models of diabetes-associated periodontitis and in vitro models of diabetic inflammation. In the in vitro co-culture model, overexpression of IL-33 in PDLFs promotes M2 macrophage polarization, while knockdown of IL-33 in PDLFs instigates M1 macrophage polarization. Notably, supplementation with IL-33 in vivosignificantly alleviates periodontal tissue destruction and enhances M2 macrophage infiltration, whereas targeting the IL-33/ST2 axis exacerbates tissue damage and promotes M1 macrophage polarization in diabetes-associated periodontitis. Additionally, theCUT&RUN assay confirms the direct regulation of IL-33 by Yes-associated protein (YAP). These findings demonstrate that IL-33 deficiency in PDLFs favors M1 macrophage polarization, thereby exacerbating the pathogenesis of diabetes-associated periodontitis. Our study underscores the essential immunomodulatory role of PDLFs in creating an inflammatory niche and unveils a novel interaction axis between PDLFs and macrophages in diabetes-associated periodontitis.
具有免疫调节特性的组织驻留成纤维细胞最近被确定为炎症中的关键参与者。然而，它们在糖尿病相关性牙周炎的牙周生态位中的作用仍不清楚。白细胞介素（IL）-33在炎症反应中被称为“警报素”，最近已成为牙周炎的一个潜在促成因素。在此，我们表明，在糖尿病相关性牙周炎的体内模型和糖尿病炎症的体外模型中，牙周膜成纤维细胞（PDLFs）中的IL-33水平降低。在体外共培养模型中，PDLFs中IL-33的过表达促进M2巨噬细胞极化，而PDLFs中IL-33的敲低则引发M1巨噬细胞极化。值得注意的是，在体内补充IL-33可显著减轻牙周组织破坏并增强M2巨噬细胞浸润，而靶向IL-33/ST2轴则会加重糖尿病相关性牙周炎中的组织损伤并促进M1巨噬细胞极化。此外，CUT&RUN分析证实Yes相关蛋白（YAP）对IL-33的直接调控。这些发现表明，PDLFs中IL-33的缺乏有利于M1巨噬细胞极化，从而加剧糖尿病相关性牙周炎的发病机制。我们的研究强调了PDLFs在创建炎症生态位中的重要免疫调节作用，并揭示了糖尿病相关性牙周炎中PDLFs与巨噬细胞之间的新型相互作用轴。
