Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, China.
J Clin Periodontol. 2023 Sep;50(9):1264-1279. doi: 10.1111/jcpe.13841. Epub 2023 Jun 27.
Necroptosis participates in the pathogenesis of many inflammatory diseases, including periodontitis. Here, we aimed to investigate the role and mechanism of necroptosis inhibitors in attenuating periodontitis.
The Gene Expression Omnibus (GEO) dataset GSE164241 was re-analysed to identify the role of necroptosis in periodontitis. Gingival specimens from healthy subjects or periodontitis patients were collected to evaluate the expression level of necroptosis-associated proteins. The therapeutic effect of necroptosis inhibitors on periodontitis was assessed in vivo and in vitro. Moreover, Transwell assays and Western blotting and siRNA transfection were used to identify the effects of necroptotic human gingival fibroblasts (hGFs) on THP-1 macrophages.
Re-analysis revealed that gingival fibroblasts (GFs) in periodontitis gingiva showed the highest area under the curve score of necroptosis. Elevated levels of necroptosis-associated proteins were identified in GFs in periodontitis gingiva collected from patients and mice. In ligature-induced periodontitis mice, local administration of receptor interacting protein kinase 3(RIPK3) inhibitor GSK'872 or sh-mixed-lineage kinase domain-like pseudokinase (Mlkl) markedly abrogated necroptosis and rescued periodontitis. Analogously, necroptosis inhibitors alleviated the inflammatory response and release of damage-associated molecular patterns in lipopolysaccharide- or LAZ (LPS + AZD'5582 + z-VAD-fmk, necroptosis inducer)-induced GFs and then reduced THP-1 cell migration and M1 polarization.
Necroptosis in GFs aggravated gingival inflammation and alveolar bone loss. Necroptosis inhibitors attenuate this process by modulating THP-1 macrophage migration and polarization. This study offers novel insights into the pathogenesis and potential therapeutic targets of periodontitis.
坏死性凋亡参与许多炎症性疾病的发病机制，包括牙周炎。本研究旨在探讨坏死性凋亡抑制剂在减轻牙周炎中的作用和机制。
重新分析基因表达综合数据库（GEO）数据集 GSE164241 以确定坏死性凋亡在牙周炎中的作用。收集健康受试者和牙周炎患者的牙龈标本，评估坏死性凋亡相关蛋白的表达水平。体内和体外评估坏死性凋亡抑制剂对牙周炎的治疗效果。此外，通过 Transwell 测定、Western blot 和 siRNA 转染来鉴定坏死性人牙龈成纤维细胞（hGFs）对 THP-1 巨噬细胞的影响。
重新分析显示，牙周炎牙龈中的成纤维细胞（GFs）具有最高的坏死性凋亡曲线下面积评分。从患者和小鼠的牙周炎牙龈中收集的 GFs 中，鉴定出坏死性凋亡相关蛋白水平升高。在结扎诱导的牙周炎小鼠中，局部给予受体相互作用蛋白激酶 3（RIPK3）抑制剂 GSK'872 或 sh-混合谱系激酶结构域样假激酶（Mlkl）可显著阻断坏死性凋亡并挽救牙周炎。类似地，坏死性凋亡抑制剂减轻了脂多糖或 LAZ（LPS+AZD'5582+z-VAD-fmk，坏死性凋亡诱导剂）诱导的 GFs 中的炎症反应和损伤相关分子模式的释放，从而减少了 THP-1 细胞的迁移和 M1 极化。
GFs 中的坏死性凋亡加重了牙龈炎症和牙槽骨丧失。坏死性凋亡抑制剂通过调节 THP-1 巨噬细胞的迁移和极化来减轻这一过程。本研究为牙周炎的发病机制和潜在治疗靶点提供了新的见解。
