Mechanical Force Triggers Macrophage Pyroptosis and Sterile Inflammation by Disrupting Cellular Energy Metabolism

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.