Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes
Abstract Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease with complex mechanism. Currently, ferroptosis is believed to play a role in it, but the specific mechanism is unknown, especially in immune response. In this study, we demonstrated that the high expression of major histocom...
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BMC
2025-03-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06300-0 |
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| author | Xiaoying Zhu Hanya Lu Haonan Jia Xuemin Wei Jiawei Xue Wenjing Li Juan Zhang Yanli Wang Jingyao Yan Haoyuan Sun Yanlei Ge Zhiyi Zhang |
| author_facet | Xiaoying Zhu Hanya Lu Haonan Jia Xuemin Wei Jiawei Xue Wenjing Li Juan Zhang Yanli Wang Jingyao Yan Haoyuan Sun Yanlei Ge Zhiyi Zhang |
| author_sort | Xiaoying Zhu |
| collection | DOAJ |
| description | Abstract Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease with complex mechanism. Currently, ferroptosis is believed to play a role in it, but the specific mechanism is unknown, especially in immune response. In this study, we demonstrated that the high expression of major histocompatibility complex I (MHC-I) molecules in RA fibroblast-like synoviocytes (FLSs) is an antigen-presenting cell property and that this property is closely related to the increase in antigens after citrullination. Moreover, we detected higher levels of ferroptosis among FLSs from RA patient than among FLSs from OA patients. Ferroptosis can increase the expression of citrullinated histone H3 (cit-h3) by promoting the production of peptidyl arginine deiminase 4 (PAD4), which further promotes the expression of MHC-I molecules. We cocultured RA-FLSs treated with ferroptosis drugs with selected CD8 + T cells to assess the effect of ferroptosis on the endogenous antigen-presenting function of RA-FLSs. Ferroptosis promoted the proliferation of CD8 + T cells and the release of the inflammatory factors Tumor necrosis factor-α (TNF-α) and Interferon-gamma (IFN-γ), which enhanced the inflammatory effect. This phenomenon was also observed in a collagen-induced arthritis (CIA) mouse model. Finally, ferrostatin-1 (fer-1), a ferroptosis inhibitor, inhibited the above effects and reduced the release of inflammatory factors, indicating that ferroptosis may play a therapeutic role in RA and providing new ideas for the treatment of RA in the field of immunity. |
| format | Article |
| id | doaj-art-25cb361cd00849a08870491cf54e3bd7 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-25cb361cd00849a08870491cf54e3bd72025-08-20T02:59:57ZengBMCJournal of Translational Medicine1479-58762025-03-0123111410.1186/s12967-025-06300-0Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytesXiaoying Zhu0Hanya Lu1Haonan Jia2Xuemin Wei3Jiawei Xue4Wenjing Li5Juan Zhang6Yanli Wang7Jingyao Yan8Haoyuan Sun9Yanlei Ge10Zhiyi Zhang11Department of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityDepartment of Osteology, Heilongjiang Provincial HospitalDepartment of Respiratory Medicine, North China University of Science and Technology Affiliated HospitalDepartment of Rheumatology, First Affiliated Hospital of Harbin Medical UniversityAbstract Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease with complex mechanism. Currently, ferroptosis is believed to play a role in it, but the specific mechanism is unknown, especially in immune response. In this study, we demonstrated that the high expression of major histocompatibility complex I (MHC-I) molecules in RA fibroblast-like synoviocytes (FLSs) is an antigen-presenting cell property and that this property is closely related to the increase in antigens after citrullination. Moreover, we detected higher levels of ferroptosis among FLSs from RA patient than among FLSs from OA patients. Ferroptosis can increase the expression of citrullinated histone H3 (cit-h3) by promoting the production of peptidyl arginine deiminase 4 (PAD4), which further promotes the expression of MHC-I molecules. We cocultured RA-FLSs treated with ferroptosis drugs with selected CD8 + T cells to assess the effect of ferroptosis on the endogenous antigen-presenting function of RA-FLSs. Ferroptosis promoted the proliferation of CD8 + T cells and the release of the inflammatory factors Tumor necrosis factor-α (TNF-α) and Interferon-gamma (IFN-γ), which enhanced the inflammatory effect. This phenomenon was also observed in a collagen-induced arthritis (CIA) mouse model. Finally, ferrostatin-1 (fer-1), a ferroptosis inhibitor, inhibited the above effects and reduced the release of inflammatory factors, indicating that ferroptosis may play a therapeutic role in RA and providing new ideas for the treatment of RA in the field of immunity.https://doi.org/10.1186/s12967-025-06300-0Rheumatoid arthritisFerroptosisImmuneAntigen presentationInflammation |
| spellingShingle | Xiaoying Zhu Hanya Lu Haonan Jia Xuemin Wei Jiawei Xue Wenjing Li Juan Zhang Yanli Wang Jingyao Yan Haoyuan Sun Yanlei Ge Zhiyi Zhang Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes Journal of Translational Medicine Rheumatoid arthritis Ferroptosis Immune Antigen presentation Inflammation |
| title | Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes |
| title_full | Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes |
| title_fullStr | Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes |
| title_full_unstemmed | Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes |
| title_short | Ferrostatin-1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast-like synoviocytes |
| title_sort | ferrostatin 1 reduces the inflammatory response of rheumatoid arthritis by decreasing the antigen presenting function of fibroblast like synoviocytes |
| topic | Rheumatoid arthritis Ferroptosis Immune Antigen presentation Inflammation |
| url | https://doi.org/10.1186/s12967-025-06300-0 |
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