College of Stomatology, Chongqing Medical University, Chongqing 401147, China.
Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China.
Int J Mol Sci. 2023 Mar 27;24(7):6309. doi: 10.3390/ijms24076309.
Macrophage pyroptosis drives the secretion of IL-1β, which has been recently reported to be a featured salivary biomarker for discriminating periodontitis in the presence of diabetes. This study aimed to explore whether macrophage pyroptosis plays a role in the development of diabetes mellitus-periodontitis, as well as potential therapeutic strategies. By establishing a model of experimental diabetes mellitus-periodontitis in rats, we found that IL-1β and gasdermin D were highly expressed, leading to aggravated destruction of periodontal tissue. MCC950, a potent and selective molecule inhibitor of the NLRP3 inflammasome, effectively inhibited macrophage pyroptosis and attenuated alveolar bone losses in diabetes mellitus-periodontitis. Consistently, in vitro, high glucose could induce macrophage pyroptosis and thus promoted IL-1β production in macrophages stimulated by lipopolysaccharide. In addition, autophagy blockade by high glucose via the mTOR-ULK1 pathway led to severe oxidative stress response in macrophages stimulated by lipopolysaccharide. Activation of autophagy by rapamycin, clearance of mitochondrial ROS by mitoTEMPO, and inhibition of inflammasome by MCC950 could significantly reduce macrophage pyroptosis and IL-1β secretion. Our study demonstrates that hyperglycemia promotes IL-1β production and pyroptosis in macrophages suffered by periodontal microbial stimuli. Modulation of autophagy activity and specific targeting of the ROS-inflammasome pathway may offer promising therapeutic strategies to alleviate diabetes mellitus-periodontitis.
巨噬细胞焦亡驱动 IL-1β 的分泌，最近有研究报道其可作为糖尿病伴牙周炎的特征性唾液生物标志物用于鉴别。本研究旨在探讨巨噬细胞焦亡是否在糖尿病伴牙周炎的发生发展中起作用，以及可能的治疗策略。通过建立大鼠实验性糖尿病伴牙周炎模型，我们发现 IL-1β 和 gasdermin D 表达上调，导致牙周组织破坏加重。NLRP3 炎性小体的强效和选择性分子抑制剂 MCC950 有效抑制了巨噬细胞焦亡，减轻了糖尿病伴牙周炎中的牙槽骨丢失。一致地，在体外，高葡萄糖可诱导巨噬细胞焦亡，从而促进脂多糖刺激的巨噬细胞中 IL-1β 的产生。此外，高葡萄糖通过 mTOR-ULK1 通路抑制自噬，导致脂多糖刺激的巨噬细胞发生严重的氧化应激反应。雷帕霉素激活自噬、mitoTEMPO 清除线粒体 ROS 以及 MCC950 抑制炎性小体均可显著减少巨噬细胞焦亡和 IL-1β 的分泌。本研究表明，高血糖促进了受牙周微生物刺激的巨噬细胞中 IL-1β 的产生和焦亡。调节自噬活性和靶向 ROS-炎性小体途径可能为减轻糖尿病伴牙周炎提供有前景的治疗策略。
