Could Trained Immunity Impact Periapical Healing? A Biological Perspective

AIM: To explore whether trained immunity, a form of innate immune memory mediated by epigenetic and metabolic reprogramming, may influence periapical healing following root canal treatment. SUMMARY: Apical periodontitis is primarily driven by microbial infection; however, healing outcomes following root canal treatment often demonstrate substantial variability despite comparable microbial reduction and treatment quality. Trained immunity has emerged as a biological phenomenon whereby prior microbial or inflammatory exposure can induce long-term functional reprogramming of innate immune cells, resulting in altered responses to subsequent challenges. This perspective examines whether previous inflammatory episodes within periapical tissues may generate a state of immune priming capable of modifying healing trajectories. Potential mechanisms include macrophage reprogramming, altered cytokine signalling, enhanced osteoclastogenesis, and disruption of the transition from inflammation to tissue repair. Retreatment lesions and chronic periapical inflammation may represent clinically relevant models for investigating the effects of inflammatory memory within endodontic disease. Whilst microbial control remains fundamental to successful treatment, trained immunity may provide a complementary framework for understanding variability in healing outcomes. CONCLUSIONS: Trained immunity represents a novel immunological concept whereby innate immune cells undergo long-term functional reprogramming following previous microbial or inflammatory exposure. Although currently unproven in endodontics, this phenomenon may provide a biologically plausible explanation for some of the variability observed in periapical healing following root canal treatment. Potential mechanisms include persistent macrophage activation, dysregulated cytokine signalling, and enhanced osteoclastogenic activity, all of which may influence inflammatory resolution and bone repair. Importantly, trained immunity should be viewed as a complementary biological framework rather than an alternative to the established infection-centred paradigm of apical periodontitis. Further experimental, translational, and clinical studies are required to determine whether inflammatory memory contributes to differences in healing outcomes and to clarify its potential relevance to future endodontic research and therapy.