HDAC3 Regulates Gingival Fibroblast Inflammatory Responses in Periodontitis.

Area of Science:

• Molecular Biology
• Immunology
• Pharmacology

Background:

• Histone deacetylases (HDACs) regulate gene expression and are implicated in inflammatory diseases.
• Gingival fibroblasts (GFs) and *Porphyromonas gingivalis* drive periodontitis inflammation.
• HDAC inhibitors (HDACi) show potential in ameliorating inflammatory conditions.

Purpose of the Study:

• To investigate the role of HDACs in the inflammatory responses of GFs.
• To determine the specific HDACs involved in *P. gingivalis*-induced inflammation in GFs.
• To evaluate the therapeutic potential of HDAC inhibition in periodontal disease.

Main Methods:

• Treatment of healthy and periodontitis patient GFs with pan-HDACi (SAHA, givinostat) and selective HDAC inhibitors.
• Stimulation with TNFα and *P. gingivalis*.
• Analysis of inflammatory mediator expression (mRNA and protein) and cell viability.
• HDAC3 gene silencing using siRNA.
• Assessment of bacterial internalization and signaling pathways (MAPK, NFκB).

Main Results:

• Pan-HDACi and HDAC3/6 inhibition suppressed TNFα- and *P. gingivalis*-inducible inflammatory mediators (e.g., IL1B, CCL2, MMP3) in healthy GFs without affecting cell viability.
• Selective inhibition of HDAC3/6, but not other specific HDACs, mimicked pan-HDACi effects, highlighting HDAC3's critical role.
• HDAC3 silencing recapitulated these suppressive effects.
• *P. gingivalis* internalization and survival were unaffected by HDACi.
• HDACi suppressed inflammatory gene expression in GFs from periodontitis patients.

Conclusions:

• HDAC3 is a key regulator of inflammatory gene expression in GFs during *P. gingivalis* infection.
• HDAC inhibition, particularly targeting HDAC3, effectively reduces inflammatory responses in GFs.
• Targeting HDAC activity, especially HDAC3, presents a promising therapeutic strategy for managing periodontal disease inflammation.