HDAC6-Mediated FoxO1 Acetylation And Phosphorylation Control Periodontal Inflammatory Responses.

Area of Science:

• Molecular Biology
• Immunology
• Oral Biology

Background:

• Post-translational modifications (PTMs) regulate protein function, but the role of specific histone deacetylases (HDACs) in non-histone protein modulation during infection is unclear.
• Periodontal disease involves complex inflammatory processes influenced by pathogen interactions and host immune responses.

Purpose of the Study:

• To investigate the role of HDAC6 in regulating periodontal inflammation induced by *Porphyromonas gingivalis*.
• To elucidate the mechanisms by which HDAC6 modulates inflammatory signaling pathways, specifically focusing on FoxO1.

Main Methods:

• Utilized *Porphyromonas gingivalis* infection models in cell cultures and mice.
• Assessed protein acetylation and phosphorylation of FoxO1 in response to HDAC6 modulation.
• Analyzed cytokine production, macrophage polarization, and inflammatory cell infiltration.
• Evaluated alveolar bone loss in periodontitis models.

Main Results:

• HDAC6 activation was induced by *P. gingivalis* infection, promoting inflammation.
• HDAC6 depletion increased FoxO1 acetylation and phosphorylation, leading to its cytoplasmic sequestration and reduced pro-inflammatory cytokine production.
• HDAC6 deficiency upregulated Rictor, enhancing mTORC2-Akt signaling and FoxO1 phosphorylation.
• HDAC6 inhibition suppressed inflammatory mediators, promoted M2 macrophage polarization, reduced gingival inflammation, and protected against bone loss in vivo.

Conclusions:

• HDAC6 is a key regulator of periodontal inflammation, orchestrating inflammatory responses through coordinated modulation of FoxO1 acetylation and phosphorylation.
• HDAC6 represents a potential therapeutic target for inflammatory diseases associated with immune dysregulation.