Porphyromonas gingivalis Induces Trained Immunity in Macrophages Through KDM6B-Dependent Demethylation of H3K27me3

Introduction and aims Periodontitis is associated with systemic inflammatory comorbidities, but how periodontal pathogens promote persistent inflammatory susceptibility remains unclear. Trained immunity can endow innate immune cells with a durable proinflammatory state. This study investigated whether Porphyromonas gingivalis induces trained immunity in macrophages and defined the underlying epigenetic pathway. Methods Trained immunity was induced in macrophages by P. gingivalis priming, followed by a resting phase and secondary stimulation. Mice received oral P. gingivalis application, and inflammatory responses in bone marrow-derived macrophages were examined ex vivo. Transcriptomic screening, western blotting, immunofluorescence, chromatin immunoprecipitation-qPCR, pharmacological inhibition, and siRNA-mediated Kdm6b knockdown were used to assess epigenetic signalling, with a focus on the histone demethylase KDM6B and the repressive histone modification H3K27me3. Bone marrow transplantation followed by dextran sulphate sodium-induced colitis was used to determine whether bone marrow from P. gingivalis -exposed mice could aggravate inflammatory disease in recipient mice. Results P. gingivalis induced a trained immunity phenotype in macrophages, characterized by enhanced production of IL-1β, IL-6, and TNF-α upon secondary stimulation. Mechanistically, P. gingivalis increased KDM6B expression through nuclear factor-kappa B (NF-κB) activation and caused a sustained reduction in H3K27me3 at key inflammatory gene promoters. Inhibition of either NF-κB or KDM6B prevented this epigenetic remodelling and attenuated the trained inflammatory response. In vivo, transplantation of P. gingivalis -trained bone marrow exacerbated dextran sulphate sodium-induced colitis, whereas inhibition of the NF-κB and KDM6B pathway during training reduced disease severity. Conclusion P. gingivalis induces macrophage trained immunity through NF-κB-dependent KDM6B activation and H3K27me3 remodelling, leading to exaggerated proinflammatory responses upon restimulation. Clinical relevance This study provides experimental evidence that P. gingivalis exposure may influence systemic inflammatory responses through macrophage reprogramming in preclinical models. These findings offer a possible mechanistic perspective on the association between periodontitis and inflammatory comorbidities.