HDAC6-Mediated FoxO1 Acetylation And Phosphorylation Control Periodontal Inflammatory Responses

Post-translational modifications (PTMs) are critical regulators of protein function and cellular signaling. While histone deacetylation by histone deacetylases (HDACs) is well established, the role of specific HDACs in modulating non-histone protein PTMs, particularly in an infectious context, is poorly understood. Here, we reveal a pivotal role for HDAC6 in orchestrating periodontal inflammation through its dual regulatory effects on FoxO1 acetylation and phosphorylation. Using Porphyromonas gingivalis, a key periodontal pathogen, as a model pathogen, we observed that infection induces HDAC6 activation, driving inflammatory responses via modulating FoxO1 activity. HDAC6 depletion increased FoxO1 acetylation and phosphorylation, leading to its cytoplasmic sequestration and subsequent suppression of FoxO1- mediated pro-inflammatory cytokine production in macrophages. Mechanistically, HDAC6 deficiency not only directly enhances the acetylation of FoxO1 but also upregulates the expression of Rictor, a critical component of the mTORC2 complex, thereby promoting Akt phosphorylation and subsequently FoxO1 phosphorylation. This results in its cytoplasmic retention and attenuated inflammatory transcriptional activity. Functional studies demonstrated that HDAC6 depletion suppressed the production of key inflammatory mediators, including TNF, IL-6, IL-12p40, and MIP-2, while promoting macrophage polarization toward anti-inflammatory M2 phenotypes. In vivo, using oral gavage infection and ligature-induced mouse periodontitis models, HDAC6 deficiency significantly reduced inflammatory cell infiltration in gingival tissues and protected against alveolar bone loss. These findings establish HDAC6 as a central regulator of periodontal inflammation, acting through the coordinated modulation of FoxO1 acetylation and phosphorylation. Beyond its role in oral pathology, HDAC6 may serve as a promising therapeutic target for managing inflammatory diseases linked to immune dysregulation.