Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling
Abstract Background Iguratimod (IGU) reduces hypergammaglobulinemia and disease activity in pSS (primary Sjögren’s syndrome) patients. However, the therapeutical mechanism of IGU for pSS remains largely unknown. This study aimed to investigate the regulation of Tfh cell differentiation by IGU in pSS...
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13075-023-03109-4 |
| _version_ | 1797451876793319424 |
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| author | Taibiao Lyu Hui Jiang Liuting Zeng Suying Liu Chengmei He Chaowen Luo Lin Qiao Yan Zhao Hua Chen |
| author_facet | Taibiao Lyu Hui Jiang Liuting Zeng Suying Liu Chengmei He Chaowen Luo Lin Qiao Yan Zhao Hua Chen |
| author_sort | Taibiao Lyu |
| collection | DOAJ |
| description | Abstract Background Iguratimod (IGU) reduces hypergammaglobulinemia and disease activity in pSS (primary Sjögren’s syndrome) patients. However, the therapeutical mechanism of IGU for pSS remains largely unknown. This study aimed to investigate the regulation of Tfh cell differentiation by IGU in pSS patients. Methods We prospectively enrolled 13 pSS patients treated with IGU for 3 months and examined circulating T cell and B cell subsets by flow cytometry. We measured Tfh cell differentiation treated by IGU in pSS patients and healthy controls. Transcriptome analysis combined with molecular docking were employed to identify potential therapeutical targets of IGU, which were verified by Western blot and Tfh cell differentiation. Results Tfh, plasmablast, and plasma cells were suppressed by IGU treatment at 1 and 3 months. Tfh cell differentiation and function were significant inhibited by IGU in pSS patients and healthy controls in vitro. Pyruvate dehydrogenase kinase 1 (PDK1) was identified as a target of IGU during Tfh cell differentiation, and the downstream Akt phosphorylation was attenuated by IGU. Moreover, the activity of mTORC1 and phosphorylation of STAT3 were suppressed by IGU, with downregulation of BCL6 and upregulation of PRDM1. Finally, Akt activator restored IGU-suppressed Tfh cell differentiation. Conclusions IGU suppresses Tfh cell differentiation in pSS patients through interacting with PDK1 and suppressing Akt-mTOR-STAT3 signaling. |
| first_indexed | 2024-03-09T15:00:46Z |
| format | Article |
| id | doaj.art-20ce3f72143d4090bebdbd7ba94eab55 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-03-09T15:00:46Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-20ce3f72143d4090bebdbd7ba94eab552023-11-26T13:54:51ZengBMCArthritis Research & Therapy1478-63622023-08-0125111110.1186/s13075-023-03109-4Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signalingTaibiao Lyu0Hui Jiang1Liuting Zeng2Suying Liu3Chengmei He4Chaowen Luo5Lin Qiao6Yan Zhao7Hua Chen8Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeAbstract Background Iguratimod (IGU) reduces hypergammaglobulinemia and disease activity in pSS (primary Sjögren’s syndrome) patients. However, the therapeutical mechanism of IGU for pSS remains largely unknown. This study aimed to investigate the regulation of Tfh cell differentiation by IGU in pSS patients. Methods We prospectively enrolled 13 pSS patients treated with IGU for 3 months and examined circulating T cell and B cell subsets by flow cytometry. We measured Tfh cell differentiation treated by IGU in pSS patients and healthy controls. Transcriptome analysis combined with molecular docking were employed to identify potential therapeutical targets of IGU, which were verified by Western blot and Tfh cell differentiation. Results Tfh, plasmablast, and plasma cells were suppressed by IGU treatment at 1 and 3 months. Tfh cell differentiation and function were significant inhibited by IGU in pSS patients and healthy controls in vitro. Pyruvate dehydrogenase kinase 1 (PDK1) was identified as a target of IGU during Tfh cell differentiation, and the downstream Akt phosphorylation was attenuated by IGU. Moreover, the activity of mTORC1 and phosphorylation of STAT3 were suppressed by IGU, with downregulation of BCL6 and upregulation of PRDM1. Finally, Akt activator restored IGU-suppressed Tfh cell differentiation. Conclusions IGU suppresses Tfh cell differentiation in pSS patients through interacting with PDK1 and suppressing Akt-mTOR-STAT3 signaling.https://doi.org/10.1186/s13075-023-03109-4Primary Sjögren’s syndromeIguratimodFollicular helper T cell |
| spellingShingle | Taibiao Lyu Hui Jiang Liuting Zeng Suying Liu Chengmei He Chaowen Luo Lin Qiao Yan Zhao Hua Chen Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling Arthritis Research & Therapy Primary Sjögren’s syndrome Iguratimod Follicular helper T cell |
| title | Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling |
| title_full | Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling |
| title_fullStr | Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling |
| title_full_unstemmed | Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling |
| title_short | Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling |
| title_sort | iguratimod suppresses tfh cell differentiation in primary sjogren s syndrome patients through inhibiting akt mtor stat3 signaling |
| topic | Primary Sjögren’s syndrome Iguratimod Follicular helper T cell |
| url | https://doi.org/10.1186/s13075-023-03109-4 |
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