GCN2-Mediated Integrated Stress Response Attenuates Periodontitis

Area of Science:

• Cellular Biology
• Immunology
• Oral Biology

Background:

• The integrated stress response (ISR), regulated by general control nonderepressible 2 (GCN2), is crucial for tissue homeostasis.
• The specific role of GCN2-mediated ISR in periodontitis pathogenesis is not well understood.

Purpose of the Study:

• To investigate the role of GCN2-mediated ISR in periodontitis.
• To explore the therapeutic potential of GCN2 activation in periodontitis.

Main Methods:

• Transcriptomic analysis and immunohistochemistry of human and mouse gingival biopsies.
• Utilizing a ligature-induced mouse periodontitis model and Gcn2 knockout mice.
• Bulk RNA-sequencing and in vitro assays to elucidate molecular mechanisms.

Main Results:

• GCN2-mediated ISR is activated in human and mouse periodontitis, primarily in macrophages.
• Gcn2 deficiency exacerbates gingival inflammation and bone loss in experimental periodontitis.
• Loss of GCN2 impairs autophagy and overactivates the NLRP3/CASPASE1 inflammasome pathway.

Conclusions:

• GCN2-mediated ISR plays a protective role in the oral mucosa against periodontitis.
• GCN2 activation, demonstrated by halofuginone treatment, mitigates oral inflammation and tissue destruction.
• GCN2 represents a potential therapeutic target for periodontitis treatment.