Diabetes exacerbates periodontitis by disrupting IL-33-mediated interaction between periodontal ligament fibroblasts and macrophages.

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.