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ORIGINAL RESEARCH article
Front. Cell. Infect. Microbiol.
Sec. Oral Microbes and Host
Volume 15 - 2025 | doi: 10.3389/fcimb.2025.1560155
Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways
Provisionally accepted
Kaihua Luo 1,2
Qinrui Wu 1,2
Zhengyi Li 1
Yajie Wu 1,2
Zhifei Su 1,2
Fangjie Zhou 1,2
Qinyang Li 1,2
Biao Ren 1
Yuqing Li 1
Jiyao Li 1,2*
Xian Peng 1*- 1 State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan Province, China
- 2 Department of Endodontics, West China School of Stomatology, Sichuan University, Chengdu, Sichuan Province, China
Emerging research demonstrates the regulatory effects of c-di-AMP, a bacterial-derived small molecule secondary messenger, on host immune responses and promoting resistance against infection-related diseases. This study aims to elucidate the role of c-di-AMP in the occurrence and development of periodontitis. Using model of ligation-induced periodontitis, we observed that c-di-AMP effectively alleviated alveolar bone resorption. Transcriptomic sequencing in mice gingival tissues demonstrated that treatment with c-di-AMP led to a significant upregulation of the PI3K/Akt signaling pathway and its key components, including Akt3. Concurrently, we observed an upregulation of the cGMP/PKG signaling pathway. To validate our findings, we treated gingival epithelial cells with c-di-AMP and confirmed the activation of the PI3K/Akt pathway by c-di-AMP in gingival epithelial cells. Under LPS-induced inflammation, c-di-AMP significantly suppressed the release of inflammatory factors (such as IL-6 and TNF-α) from gingival epithelial cells. Moreover, key components of the PI3K/Akt pathway, including Akt, and downstream inflammation regulatory gene Nrf2, were upregulated, which were also confirmed at the protein level. Collectively, this study demonstrates that c-di-AMP definitely plays a role in alleviating periodontitis. Our findings highlight the mechanisms by which c-di-AMP modulates periodontitis, including activating the PI3K/Akt pathway and potentially involving the cGMP/PKG pathway, ultimately contributing to improved immune defense and maintenance of bone homeostasis.
Keywords: c-di-AMP, PI3K/Akt signaling pathway, second-messenger systems, Periodontitis, Host-Pathogen Interactions, Microbial dysbiosis
Received: 14 Jan 2025; Accepted: 26 Feb 2025.
Copyright: © 2025 Luo, Wu, Li, Wu, Su, Zhou, Li, Ren, Li, Li and Peng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jiyao Li, State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, 610041, Sichuan Province, China
Xian Peng, State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, 610041, Sichuan Province, China
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