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Adiponectin inhibits ROS/NLRP3 inflammatory pathway through FOXO3A to ameliorate oral submucosal fibrosis

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Abstract

Oral submucous fibrosis (OSF) is an oral condition characterized by chronic progression, which may lead to the development of malignancy. Currently, available treatments for OSF only provide temporary relief of symptoms, and there is a limited availability of effective interventions that can effectively cure this condition. In this study, we aimed to investigate whether adiponectin (APN) could ameliorate OSF and the mechanisms involved in it. First, human oral mucosal fibroblasts (HOMFs) were cultured, an OSF model was established using arecoline, and APN and Imiquimod treatment were administered. Then we overexpressed NLRP3 and knocked down FOXO3A. FOXO3A, fibrosis-related factors (ɑ-SMA, COL1A, CTGF), TGF-β1/Smad3 signaling-related factors (TGF-β1, p-Smad3, Smad3), NLRP3 inflammasome-related factors (NLRP3, Caspase-1, IL-1β), and ROS levels were evaluated. Finally, we explored the effect of APN on OSF in mice by in vivo experiments. We found that arecoline significantly increased ɑ-SMA, COL1A, CTGF, and TGF-β1 expressions and promoted Smad3 phosphorylation, while APN significantly inhibited the elevation of these fibrosis-related factors. ROS production was significantly elevated in HOMFs after arecoline treatment, while APN treatment inhibited ROS production. However, the addition of Imiquimod and overexpression of NLRP3 exhibited a trend of elevated ROS, resisting the inhibitory effect of APN. Furthermore, adding Imiquimod and overexpression of NLRP3 elevated ɑ-SMA, COL1A and CTGF and activated TGF-β1/Smad3 signaling pathway. Additionally, knockdown of FOXO3A enhanced APN-inhibited ɑ-SMA and COL1A. In vivo experiments further confirmed that APN ameliorated OSF in mice by inhibiting ROS/NLRP3 inflammatory pathway. In conclusion, APN ameliorated arecoline-induced OSF by promoting FOXO3A expression and downregulating the ROS/NLRP3 pathway.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Clinical Medical Technology Innovation Guidance Project (No. 2021SK52004).

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Author notes

  1. $ Yuanyuan Zeng and Mengshen Luo contributed equally to this study. They are the co-first authors.

Authors and Affiliations

  1. Department of Stomatology, the Central Hospital of Shaoyang, Shaoyang, No. 36, Qianyuan Lane, Hongqi Road, Daxiang District, Shaoyang, Hunan, China

    Yuanyuan Zeng, Mengshen Luo, Zhilong Yao & Xiaoping Xiao

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Contributions

YZ and ML contributed to conceptualization, data curation, formal analysis, validation, writing of the original draft. ZY contributed to investigation, software and methodology. XX contributed to funding acquisition, project administration, supervision and review. All authors read and approved the final manuscript.

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Correspondence to Xiaoping Xiao.

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Ethics approval

This study was approved by Hunan SJA Laboratory Animal Co., Ltd. (No. SJA202302001: the license number) and conducted in strict accordance with the national institutes of health guidelines for the care and use of experimental animals.

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Zeng, Y., Luo, M., Yao, Z. et al. Adiponectin inhibits ROS/NLRP3 inflammatory pathway through FOXO3A to ameliorate oral submucosal fibrosis. Odontology 112, 811–825 (2024). https://doi.org/10.1007/s10266-023-00891-0

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