SIRT3 alleviates periodontitis inflammation by inhibiting macrophage M1 polarization regulation via FOXO3/NRF2.

Abstract

Sirtuin3 (SIRT3) is a key mitochondrial deacetylase implicated in inflammatory regulation, but its precise role in periodontitis remains to be elucidated. We investigated SIRT3 expression in human gingival tissues and employed in vitro models using bone marrow-derived macrophages (BMDMs) and RAW264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide (Pg.LPS). The mechanisms were explored through protein-protein interaction prediction, co-immunoprecipitation (co-IP), and Western blotting. In vivo, a mouse periodontitis model was established with local SIRT3 overexpression to validate our findings. We found that SIRT3 expression was significantly downregulated in periodontitis tissues. In vitro, activation of SIRT3 by honokiol suppressed LPS-induced M1 macrophage polarization and the secretion of TNF-α and IL-6. Mechanistically, bioinformatic analysis and co-IP confirmed FOXO3 as a direct binding partner of SIRT3. SIRT3 overexpression activated the FOXO3/NRF2 pathway, and this effect was reversed by FOXO3 inhibition, which also restored M1 polarization and inflammatory cytokine release. In vivo, SIRT3 overexpression in mice attenuated inflammatory cell infiltration, reduced CD45immune cells, and shifted the macrophage phenotype from M1 to M2. This was accompanied by decreased TNF-α and IL-6, activated FOXO3/NRF2 signaling, and ameliorates alveolar bone injury. In conclusion, our findings demonstrate that SIRT3 ameliorates periodontitis by suppressing M1 macrophage polarization and subsequent inflammatory responses through activation of the FOXO3/NRF2 axis, highlighting its potential as a novel therapeutic target for periodontal disease.