Fibroblast-derived exosomes induce macrophage pyroptosis to mediate orthodontic bone remodeling through the mtDNA/NLRP3 axis

Orthodontic bone remodeling relies on the integration of mechanotransduction and osteoimmunological crosstalk. Mitochondria, as central regulators of both mechanical sensing and immune modulation, play increasingly recognized roles in force-induced inflammation. Exosomes are nanoscale extracellular vesicles that facilitate the cell-to-cell transport of substances. Investigating the role of exosomes in mitochondrial component transfer may provide new insights into fibroblast‒macrophage communication in orthodontics. In this study, we found that mechanical compression induced oxidative stress and aberrant release of mitochondrial DNA (mtDNA) in periodontal ligament fibroblasts (PDLFs). Further experiments verified that cytosolic mtDNA in PDLFs was packaged into exosomes and secreted extracellularly. Upon phagocytosis of these mtDNA-enriched exosomes, macrophages initiate NLRP3-dependent pyroptosis, which further amplifies the local inflammatory response and induces alveolar bone remodeling. Knockout of the Casp1/11 or Nlrp3 gene in mice, blockade of exosome secretion via local injection of GW4869, or alleviation of oxidative stress via oral administration of NAC helped attenuate macrophage pyroptosis and suppress orthodontic bone remodeling. This study suggests that exosome-mediated mtDNA transfer plays a role in regulating orthodontic force-related inflammation. Our findings provide novel insights into the communication between mechanosensitive and immune cells and propose a potential therapeutic strategy for modulating the rate of tooth movement and managing oral mechanically associated inflammation.