KAT3B-mediated succinylation of DERL3 suppresses osteogenic differentiation by promoting M1/M2 macrophage polarization

Periodontitis is a chronic inflammatory disease influenced by macrophage polarization. Additionally, succinylation-enriched Porphyromonas gingivalis is a pathogenic factor of periodontitis. However, the role of succinylation in the pathogenesis of periodontitis remains unclear. This study aimed to investigate the effects of a succinyltransferase KAT3B on macrophage polarization, osteogenic differentiation, and the molecular mechanism. Macrophages RAW264.7 were cocultured with MC3T3-E1-differentiated osteoblasts, and macrophage polarization and osteogenic differentiation were evaluated. iTRAQ-based proteomic analysis identified that DERL3 was highly expressed in lipopolysaccharide (LPS)-treated MC3T3-E1 cells. The TLR4/MyD88 pathway is closely related to inflammatory response. Thus, the succinylation of DERL3 and the TLR4/MyD88 pathway were assessed using immunoblotting. The results showed that KAT3B-mediated succinylation was increased in LPS-treated MC3T3-E1 cells and patients with periodontitis. Knockdown of KAT3B inhibited macrophage M1-like polarization and promoted M2-like polarization, thereby promoting osteogenic differentiation in LPS-treated osteoblasts. Mechanically, overexpression of KAT3B promoted the succinylation of DERL3 and stabilized this protein, thereby upregulating DERL3 expression. Rescue experiments showed that DERL3 reversed the promotion of osteogenic differentiation and M2/M1 macrophage polarization caused by KAT3B knockdown. Moreover, DERL3 activated the TLR4/MyD88 pathway, and inhibition of this pathway reversed macrophage polarization and osteogenesis mediated by DERL3. In vivo experiments showed that KAT3B knockdown attenuated experimental periodontitis in rats. In conclusion, silencing of KAT3B promotes osteogenic differentiation by inducing M2/M1 macrophage polarization through the succinylation DERL3, which regulates the TLR4/MyD88 pathway, thereby attenuating periodontitis. These findings suggest that KAT3B may be a promising therapeutic target for periodontitis.

DERL3; KAT3B; Macrophage polarization; Osteogenic differentiation; Succinylation; TLR4/MyD88 pathway.