Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways
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 peri...
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1560155/full |
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| author | Kaihua Luo Kaihua Luo Qinrui Wu Qinrui Wu Zhengyi Li Yajie Wu Yajie Wu Zhifei Su Zhifei Su Fangjie Zhou Fangjie Zhou Qinyang Li Qinyang Li Biao Ren Yuqing Li Jiyao Li Jiyao Li Xian Peng |
| author_facet | Kaihua Luo Kaihua Luo Qinrui Wu Qinrui Wu Zhengyi Li Yajie Wu Yajie Wu Zhifei Su Zhifei Su Fangjie Zhou Fangjie Zhou Qinyang Li Qinyang Li Biao Ren Yuqing Li Jiyao Li Jiyao Li Xian Peng |
| author_sort | Kaihua Luo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-dd36b07d19fd4231ba1d40c80f096076 |
| institution | DOAJ |
| issn | 2235-2988 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj-art-dd36b07d19fd4231ba1d40c80f0960762025-08-20T02:53:13ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882025-03-011510.3389/fcimb.2025.15601551560155Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathwaysKaihua Luo0Kaihua Luo1Qinrui Wu2Qinrui Wu3Zhengyi Li4Yajie Wu5Yajie Wu6Zhifei Su7Zhifei Su8Fangjie Zhou9Fangjie Zhou10Qinyang Li11Qinyang Li12Biao Ren13Yuqing Li14Jiyao Li15Jiyao Li16Xian Peng17State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaState Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, ChinaEmerging 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.https://www.frontiersin.org/articles/10.3389/fcimb.2025.1560155/fullc-di-AMPPI3K/Akt signaling pathwaysecond-messenger systemsperiodontitishost-pathogen interactionsmicrobial dysbiosis |
| spellingShingle | Kaihua Luo Kaihua Luo Qinrui Wu Qinrui Wu Zhengyi Li Yajie Wu Yajie Wu Zhifei Su Zhifei Su Fangjie Zhou Fangjie Zhou Qinyang Li Qinyang Li Biao Ren Yuqing Li Jiyao Li Jiyao Li Xian Peng Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways Frontiers in Cellular and Infection Microbiology c-di-AMP PI3K/Akt signaling pathway second-messenger systems periodontitis host-pathogen interactions microbial dysbiosis |
| title | Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways |
| title_full | Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways |
| title_fullStr | Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways |
| title_full_unstemmed | Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways |
| title_short | Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways |
| title_sort | cyclic di amp alleviates periodontitis by activating pi3k akt nrf2 pathways |
| topic | c-di-AMP PI3K/Akt signaling pathway second-messenger systems periodontitis host-pathogen interactions microbial dysbiosis |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1560155/full |
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