A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalance
IntroductionDysfunctional self-tolerance is thought to play a crucial role in the onset of rheumatoid arthritis (RA) pathogenesis. Poorly functioning regulatory T cells (Tregs) lead to extreme situations where self-tolerance is robustly disrupted. However, there are many uncertainties regarding its...
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Frontiers Media S.A.
2025-05-01
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| author | Ping Li Ping Li Xin Yin Xinzhu Wen Xuyu Li Yuqing Wang Hongyan Zhan Hanqing Che Chunsuo Yao Qi Hou Ziqian Zhang Ruifang Zheng Mingbao Lin |
| author_facet | Ping Li Ping Li Xin Yin Xinzhu Wen Xuyu Li Yuqing Wang Hongyan Zhan Hanqing Che Chunsuo Yao Qi Hou Ziqian Zhang Ruifang Zheng Mingbao Lin |
| author_sort | Ping Li |
| collection | DOAJ |
| description | IntroductionDysfunctional self-tolerance is thought to play a crucial role in the onset of rheumatoid arthritis (RA) pathogenesis. Poorly functioning regulatory T cells (Tregs) lead to extreme situations where self-tolerance is robustly disrupted. However, there are many uncertainties regarding its immunosuppressive pathways, especially concerning therapeutic drugs that are still in their infancy. Therefore, deciphering potential targets and developing novel drugs to ameliorate functional Tregs deficiency appears to be an efficient therapeutic approach for controlling RA.MethodsThe therapeutic effects of EIE-2, a novel 3-arylbenzofuran derivative, were evaluated in collagen-induced arthritis (CIA) rats and carrageenan-induced paw edema mice in vivo, as well as in LPS-, PMA- or TNF-α-stimulated human CD4+ T cells (Jurkat), human synovial sarcoma cells (SW982) and primary isolated lymphocytes in vitro. The role of Syk in Treg-dependent tolerance and the mechanism of EIE-2 were explored using western blotting, quantitative reverse transcription PCR (qRT-PCR) and flow cytometry. Potential mechanistic targets were further validated through siRNA knockdown and molecular docking analysis.ResultsEIE-2 significantly ameliorated arthritic symptoms and pathological damage in CIA rats by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors in synovium and serum, and exhibited similar therapeutic effects in carrageenan-induced pedal edema mice. Moreover, EIE-2 potently suppressed the inflammatory responses in human synoviocyte SW982 cells, primary isolated lymphocytes and CD4+ Jurkat cells. Its therapeutic potential was associated with upregulation of Tregs during the active phase and downregulation during the inactive phase of RA. Mechanistically, EIE-2 modulated the PKCθ/mTOR ratio via Syk targeting, thereby restoring homeostasis in Tregs.DiscussionEIE-2 is a potential therapeutic candidate for RA. The underlying mechanism may involve its targeting on Syk to upregulate the PKCθ/mTOR ratio during the active phase of RA and downregulate the PKCθ/mTOR ratio during the inactive phase of RA, ultimately promoting Treg-dependent tolerance restoration. |
| format | Article |
| id | doaj-art-bba3009ac1cb4d258ed0e8dfe062cb43 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
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| series | Frontiers in Immunology |
| spelling | doaj-art-bba3009ac1cb4d258ed0e8dfe062cb432025-08-20T02:33:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15244911524491A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalancePing Li0Ping Li1Xin Yin2Xinzhu Wen3Xuyu Li4Yuqing Wang5Hongyan Zhan6Hanqing Che7Chunsuo Yao8Qi Hou9Ziqian Zhang10Ruifang Zheng11Mingbao Lin12Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaNHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Pharmacy Department, Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaXinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaIntroductionDysfunctional self-tolerance is thought to play a crucial role in the onset of rheumatoid arthritis (RA) pathogenesis. Poorly functioning regulatory T cells (Tregs) lead to extreme situations where self-tolerance is robustly disrupted. However, there are many uncertainties regarding its immunosuppressive pathways, especially concerning therapeutic drugs that are still in their infancy. Therefore, deciphering potential targets and developing novel drugs to ameliorate functional Tregs deficiency appears to be an efficient therapeutic approach for controlling RA.MethodsThe therapeutic effects of EIE-2, a novel 3-arylbenzofuran derivative, were evaluated in collagen-induced arthritis (CIA) rats and carrageenan-induced paw edema mice in vivo, as well as in LPS-, PMA- or TNF-α-stimulated human CD4+ T cells (Jurkat), human synovial sarcoma cells (SW982) and primary isolated lymphocytes in vitro. The role of Syk in Treg-dependent tolerance and the mechanism of EIE-2 were explored using western blotting, quantitative reverse transcription PCR (qRT-PCR) and flow cytometry. Potential mechanistic targets were further validated through siRNA knockdown and molecular docking analysis.ResultsEIE-2 significantly ameliorated arthritic symptoms and pathological damage in CIA rats by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors in synovium and serum, and exhibited similar therapeutic effects in carrageenan-induced pedal edema mice. Moreover, EIE-2 potently suppressed the inflammatory responses in human synoviocyte SW982 cells, primary isolated lymphocytes and CD4+ Jurkat cells. Its therapeutic potential was associated with upregulation of Tregs during the active phase and downregulation during the inactive phase of RA. Mechanistically, EIE-2 modulated the PKCθ/mTOR ratio via Syk targeting, thereby restoring homeostasis in Tregs.DiscussionEIE-2 is a potential therapeutic candidate for RA. The underlying mechanism may involve its targeting on Syk to upregulate the PKCθ/mTOR ratio during the active phase of RA and downregulate the PKCθ/mTOR ratio during the inactive phase of RA, ultimately promoting Treg-dependent tolerance restoration.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1524491/fullEIE-2rheumatoid arthritisTreg-dependent toleranceSykPKCθ/mTOR |
| spellingShingle | Ping Li Ping Li Xin Yin Xinzhu Wen Xuyu Li Yuqing Wang Hongyan Zhan Hanqing Che Chunsuo Yao Qi Hou Ziqian Zhang Ruifang Zheng Mingbao Lin A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalance Frontiers in Immunology EIE-2 rheumatoid arthritis Treg-dependent tolerance Syk PKCθ/mTOR |
| title | A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalance |
| title_full | A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalance |
| title_fullStr | A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalance |
| title_full_unstemmed | A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalance |
| title_short | A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalance |
| title_sort | new 3 arylbenzofuran derivative eie 2 reestablishes treg dependent tolerance in rheumatoid arthritis by targeting on syk induced mtor and pkcθ imbalance |
| topic | EIE-2 rheumatoid arthritis Treg-dependent tolerance Syk PKCθ/mTOR |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1524491/full |
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