Chen Qin, Liu Xingguang, Wang Dingyu, Zheng Jisi, Chen Lu, Xie Qianyang, Liu Xiaohan, Niu Sujuan, Qu Guanlin, Lan Jianfeng, Li Jing, Yang Chi, Zou Duohong
Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China.
National Key Laboratory of Medical Immunology, Navy Military Medical University, Shanghai, China.
Front Cell Dev Biol. 2021 Apr 1;9:663037. doi: 10.3389/fcell.2021.663037. eCollection 2021.
Periodontitis is an immune inflammatory disease that leads to progressive destruction of bone and connective tissue, accompanied by the dysfunction and even loss of periodontal ligament stem cells (PDLSCs). Pyroptosis mediated by gasdermin-D (GSDMD) participates in the pathogenesis of inflammatory diseases. However, whether pyroptosis mediates PDLSC loss, and inflammation triggered by pyroptosis is involved in the pathological progression of periodontitis remain unclear. Here, we found that PDLSCs suffered GSDMD-dependent pyroptosis to release interleukin-1β (IL-1β) during human periodontitis. Importantly, the increased IL-1β level in gingival crevicular fluid was significantly correlated with periodontitis severity. The caspase-4/GSDMD-mediated pyroptosis caused by periodontal bacteria and cytoplasmic lipopolysaccharide (LPS) dominantly contributed to PDLSC loss. By releasing IL-1β into the tissue microenvironment, pyroptotic PDLSCs inhibited osteoblastogenesis and promoted osteoclastogenesis, which exacerbated the pathological damage of periodontitis. Pharmacological inhibition of caspase-4 or IL-1β antibody blockade in a rat periodontitis model lead to the significantly reduced loss of alveolar bone and periodontal ligament damage. Furthermore, Gsdmd deficiency alleviated periodontal inflammation and bone loss in mouse experimental periodontitis. These findings indicate that GSDMD-driven PDLSC pyroptosis and loss plays a pivotal role in the pathogenesis of periodontitis by increasing IL-1β release, enhancing inflammation, and promoting osteoclastogenesis.
牙周炎是一种免疫炎症性疾病，可导致骨和结缔组织的渐进性破坏，并伴有牙周膜干细胞（PDLSCs）功能障碍甚至丧失。由gasdermin-D（GSDMD）介导的细胞焦亡参与炎症性疾病的发病机制。然而，细胞焦亡是否介导PDLSC丧失，以及细胞焦亡引发的炎症是否参与牙周炎的病理进展仍不清楚。在此，我们发现人类牙周炎期间，PDLSCs会发生依赖GSDMD的细胞焦亡以释放白细胞介素-1β（IL-1β）。重要的是，龈沟液中升高的IL-1β水平与牙周炎严重程度显著相关。由牙周细菌和细胞质脂多糖（LPS）引起的caspase-4/GSDMD介导的细胞焦亡是导致PDLSC丧失的主要原因。通过将IL-1β释放到组织微环境中，发生细胞焦亡的PDLSCs抑制成骨细胞生成并促进破骨细胞生成，从而加剧了牙周炎的病理损伤。在大鼠牙周炎模型中，对caspase-4进行药理学抑制或用IL-1β抗体阻断可显著减少牙槽骨丧失和牙周韧带损伤。此外，Gsdmd基因缺陷减轻了小鼠实验性牙周炎中的牙周炎症和骨质流失。这些发现表明，GSDMD驱动的PDLSC细胞焦亡和丧失通过增加IL-1β释放、增强炎症和促进破骨细胞生成，在牙周炎发病机制中起关键作用。
