Abstract
Periodontitis, delineated by the destruction of structures that support teeth, is predominantly propelled by intricate immune responses. Immunomodulatory treatments offer considerable promise for the management of this ailment; however, the modulation of the periodontal immune microenvironment to facilitate tissue regeneration presents a substantial biomedical challenge. Herein, our study investigates the role of Wilms' tumor 1-associating protein (WTAP), a critical m6A methyltransferase, in the immunomodulation of periodontitis and assesses its viability as a therapeutic target. We observed heightened expression of WTAP in macrophages extracted from gingival tissues impacted by periodontitis, with a strong association with M1 polarization. Via loss-of-function experiments, we demonstrated that diminishing WTAP expression precipitates a transition from M1 to M2 macrophage phenotypes amidst inflammatory conditions, thus improving the periodontal immune landscape. Further, RNA sequencing and indirect co-culture assays indicated that suppressing of WTAP expression modulates osteoimmune responses and enhances the osteogenic differentiation of bone marrow stromal cells. The local deployment of adeno-associated virus-shWTAP in murine models of periodontitis robustly validated the therapeutic promise of targeting WTAP in this disease. Collectively, our findings highlight the crucial role of WTAP in orchestrating macrophage-mediated osteoimmune responses and tissue regeneration in periodontitis, proposing novel avenues for immunotherapeutic interventions in its treatment.