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ROS-Induced Gingival Fibroblast Senescence: Implications in Exacerbating Inflammatory Responses in Periodontal Disease

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Abstract

Periodontal disease is the pathological outcome of the overwhelming inflammation in periodontal tissue. Cellular senescence has been associated with chronic inflammation in several diseases. However, the role of cellular senescence in the pathogenesis of periodontal disease remained unclear. This study aimed to investigate the role and the mechanism of cellular senescence in periodontal disease. Using single-cell RNA sequencing, we first found the upregulated level of cellular senescence in fibroblasts and endothelial cells from inflamed gingival tissue. Subsequently, human gingival fibroblasts isolated from healthy and inflamed gingival tissues were labeled as H-GFs and I-GFs, respectively. Compared to H-GFs, I-GFs exhibited a distinct cellular senescence phenotype, including an increased proportion of senescence-associated β-galactosidase (SA-β-gal) positive cells, enlarged cell morphology, and significant upregulation of p16INK4A expression. We further observed increased cellular reactive oxygen species (ROS) activity, mitochondrial ROS, and DNA damage of I-GFs. These phenotypes could be reversed by ROS scavenger NAC, which suggested the cause of cellular senescence in I-GFs. The migration and proliferation assay showed the decreased activity of I-GFs while the gene expression of senescence-associated secretory phenotype (SASP) factors such as IL-1β, IL-6, TGF-β, and IL-8 was all significantly increased. Finally, we found that supernatants of I-GF culture induced more neutrophil extracellular trap (NET) formation and drove macrophage polarization toward the CD86-positive M1 pro-inflammatory phenotype. Altogether, our findings implicate that, in the inflamed gingiva, human gingival fibroblasts acquire a senescent phenotype due to oxidative stress-induced DNA and mitochondrial damage, which in turn activate neutrophils and macrophages through the secretion of SASP factors.

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Data Availability

Sequence data that support the findings of this study will be made available on request.

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Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 82071095 and 32370816). The authors assert that AI techniques should be utilized solely to enhance readability and language rather than replace critical research tasks.

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  1. Shuling Guo and Liangliang Fu are contribute equally to this work.

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  1. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China

    Shuling Guo, Liangliang Fu, Chenghu Yin, Wenjun Shao, Quan Sun, Liangwen Chen, Ting Xia, Min Wang & Haibin Xia

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Contributions

S.G. and L.F.: conceptualization, formal analysis, investigation, project administration, validation, visualization, and writing—original draft. C.Y. and W.S.: data curation, methodology, and resources. Q.S., L.C., and T.X.: investigation, resources, and validation. M.W. and H.X.: conceptualization, data curation, formal analysis, funding acquisition, project administration, supervision, and writing—review and editing.

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Correspondence to Min Wang or Haibin Xia.

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Guo, S., Fu, L., Yin, C. et al. ROS-Induced Gingival Fibroblast Senescence: Implications in Exacerbating Inflammatory Responses in Periodontal Disease. Inflammation (2024). https://doi.org/10.1007/s10753-024-02014-5

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