AIM2-mediated senescence of gingival fibroblasts exacerbates inflammaging in periodontitis

Dec 28, 2025Free radical biology & medicine

How AIM2 triggers aging in gum cells and worsens inflammation in gum disease

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Abstract

Periodontitis tissues showed 2.7-fold upregulation of AIM2 in the epithelium compared to healthy controls.

Higher AIM2 levels in periodontitis are associated with increased inflammation markers, including caspase-1 and IL-1β.
AIM2 correlates positively with clinical measures of periodontal disease, such as bleeding on probing and attachment loss.
AIM2 overexpression in human gingival fibroblasts leads to increased expression of the senescence marker p16 and enhanced reactive oxygen species (ROS) production.
Knockdown of AIM2 in fibroblasts reverses these effects, indicating a shift towards a survival-senescence phenotype.
RNA sequencing reveals that AIM2 overexpression enriches pathways related to inflammation, suggesting its role in regulating inflammatory responses and cellular aging.
AIM2 may play a central role in linking DNA damage and senescence signaling, contributing to chronic inflammation in periodontitis.

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To explore how AIM2 contributes to inflammation-associated senescence in gingival fibroblasts and to clarify its role in periodontal tissue deterioration, gingival tissues from healthy controls and periodontitis patients were subjected to multiplex immunofluorescence staining to assess AIM2, the DNA damage marker γH2AX, the senescence marker p16, and inflammatory mediators including IL-6, IL-1β, caspase-1, ASC, and GSDMD. Human gingival fibroblasts (hGFs) with AIM2 overexpression or siRNA-mediated knockdown were established, followed by analyses of SASP profiles, DNA damage, and alternative splicing via RNA-seq. Periodontitis tissues exhibited significantly worse periodontal parameters and showed marked AIM2 upregulation, with mean fluorescence intensity increased by 2.7-fold in the epithelium and 2.4-fold in the lamina propria compared with HC, accompanied by elevated caspase-1, GSDMD, and IL-1β. AIM2 levels correlated positively with bleeding on probing and attachment loss, and multiplex immunofluorescence revealed accumulation of AIM2/γH2AX/p16 senescent fibroblasts co-expressing IL-6 in periodontitis lesions. In hGFs, AIM2 overexpression increased p16expression and ROS while reducing apoptosis, whereas AIM2 knockdown reversed these changes, indicating a shift toward a survival-senescence phenotype with enhanced SASP. RNA sequencing of AIM2-overexpressing hGFs showed enrichment of inflammatory, ribosome/spliceosome, and p53-related pathways, together with widespread alternative splicing in genes involved in lipid metabolism, innate immunity, and DNA damage responses, linking AIM2 to coordinated transcriptional and post-transcriptional regulation of inflammaging. AIM2 therefore appears to function as a potential regulatory node integrating DNA damage and senescence signaling in gingival fibroblasts, sustaining a positive feedback loop between chronic inflammation and cellular senescence in periodontitis. Targeting AIM2 may help disrupt the inflammaging cycle and could represent a potential strategy for mitigating periodontal tissue destruction and age-related inflammatory deterioration. INK4A + + INK4A + INK4A

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AIM2-mediated senescence of gingival fibroblasts exacerbates inflammaging in periodontitis

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