Data_Sheet_1_Periodontal Inflammation-Triggered by Periodontal Ligament Stem Cell Pyroptosis Exacerbates Periodontitis.PDF

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（Periodontitis）是一种免疫炎症性疾病，可引发骨与结缔组织进行性破坏，并伴随牙周膜干细胞（periodontal ligament stem cells，PDLSCs）功能异常乃至丧失。由焦孔素D（gasdermin-D，GSDMD）介导的细胞焦亡（pyroptosis）参与诸多炎症性疾病的发病进程。然而，细胞焦亡是否介导牙周膜干细胞丧失，以及细胞焦亡触发的炎症是否参与牙周炎的病理进展，目前尚未明确。本研究发现，在人类牙周炎发生发展过程中，牙周膜干细胞会发生GSDMD依赖性细胞焦亡并释放白细胞介素1β（interleukin-1β，IL-1β）。尤为重要的是，龈沟液（gingival crevicular fluid）中IL-1β水平升高与牙周炎严重程度呈显著正相关。牙周细菌与胞质脂多糖（lipopolysaccharide，LPS）诱导的半胱天冬酶-4（caspase-4）/GSDMD介导的细胞焦亡，是牙周膜干细胞丧失的主要诱因。发生细胞焦亡的牙周膜干细胞通过将IL-1β释放至组织微环境，可抑制成骨细胞生成（osteoblastogenesis）并促进破骨细胞生成（osteoclastogenesis），进而加重牙周炎的病理损伤。在大鼠牙周炎模型中，对半胱天冬酶-4进行药理学抑制或采用IL-1β抗体阻断治疗，可显著减轻牙槽骨（alveolar bone）丧失与牙周膜损伤。此外，在小鼠实验性牙周炎模型中，Gsdmd基因缺陷可缓解牙周炎症与骨丢失。本研究结果表明，GSDMD驱动的牙周膜干细胞焦亡与丧失，通过增加IL-1β释放、增强炎症反应并促进破骨细胞生成，在牙周炎的发病机制中发挥关键作用。