Tan Hao, Yang Guoyin, Zhu Ye, He Xinyi, Yang Lan, Hu Yun, Zheng Leilei
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. 2025 Apr 2;26(7):3321. doi: 10.3390/ijms26073321.
Mechanical force regulates tissue remodeling during orthodontic tooth movement (OTM) by inducing macrophage-mediated sterile inflammatory responses. Pyroptosis, as an inflammatory form of programmed cell death, triggers a robust inflammatory cascade by activating the inflammasome. Although recent reports have demonstrated that pyroptosis can be activated by mechanical force, it remains unclear whether and how orthodontic force induces macrophage pyroptosis and sterile inflammation. In this study, by establishing a rat OTM model and a force-loaded macrophage model, we found that force induces Caspase1-dependent pyroptosis in macrophages and activates sterile inflammation both in vivo and in vitro. Mechanistically, we uncovered that mechanical force disrupts macrophage energy metabolism, characterized by an imbalance between lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase (PDH), as well as mitochondrial dysfunction. Notably, inhibiting pyruvate dehydrogenase kinase 1 (PDK1) effectively restored this metabolic balance, thereby alleviating pyroptosis and sterile inflammation in force-stimulated macrophages. Overall, this study elucidates that force induces macrophage pyroptosis and sterile inflammation, and further identifies imbalances in the LDHA/PDH ratio and mitochondrial dysfunction as pivotal mechanistic features. These insights offer novel perspectives and potential therapeutic targets for the precise and effective modulation of OTM.
机械力通过诱导巨噬细胞介导的无菌性炎症反应来调节正畸牙齿移动（OTM）过程中的组织重塑。细胞焦亡作为程序性细胞死亡的一种炎症形式，通过激活炎性小体触发强烈的炎症级联反应。尽管最近的报道表明细胞焦亡可被机械力激活，但正畸力是否以及如何诱导巨噬细胞焦亡和无菌性炎症仍不清楚。在本研究中，通过建立大鼠OTM模型和力加载巨噬细胞模型，我们发现力在体内和体外均可诱导巨噬细胞中依赖半胱天冬酶1的细胞焦亡并激活无菌性炎症。机制上，我们发现机械力破坏巨噬细胞能量代谢，其特征为乳酸脱氢酶A（LDHA）与丙酮酸脱氢酶（PDH）之间失衡以及线粒体功能障碍。值得注意的是，抑制丙酮酸脱氢酶激酶1（PDK1）可有效恢复这种代谢平衡，从而减轻力刺激巨噬细胞中的细胞焦亡和无菌性炎症。总体而言，本研究阐明了力可诱导巨噬细胞焦亡和无菌性炎症，并进一步确定LDHA/PDH比值失衡和线粒体功能障碍为关键的机制特征。这些见解为精确有效地调节OTM提供了新的视角和潜在的治疗靶点。
