MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway
Abstract The involvement of B lymphocytes in the pathogenesis of rheumatoid arthritis (RA) is well-established, with their early and aberrant activation being a crucial factor. However, the mechanisms underlying this abnormal activation in RA remain incompletely understood. In this study, we identif...
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| Format: | Article |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07352-2 |
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| author | Pei Huang Guangli Yang Pingping Zhang Yin Zhu Yaning Guan Jian Sun Qian Li Yang An Xiaoqi Shi Juanjuan Zhao Chaohong Liu Zhixu He Yan Chen Zuochen Du |
| author_facet | Pei Huang Guangli Yang Pingping Zhang Yin Zhu Yaning Guan Jian Sun Qian Li Yang An Xiaoqi Shi Juanjuan Zhao Chaohong Liu Zhixu He Yan Chen Zuochen Du |
| author_sort | Pei Huang |
| collection | DOAJ |
| description | Abstract The involvement of B lymphocytes in the pathogenesis of rheumatoid arthritis (RA) is well-established, with their early and aberrant activation being a crucial factor. However, the mechanisms underlying this abnormal activation in RA remain incompletely understood. In this study, we identified a significant reduction in MAPK4 expression in both RA patients and collagen-induced arthritis (CIA) mouse models, which correlates with disrupted B cell activation. Using MAPK4 knockout (KO) mice, we demonstrated that MAPK4 intrinsically promotes the differentiation of marginal zone (MZ) B cells. Loss of MAPK4 in KO mice enhances proximal BCR signaling and activates the PI3K-AKT-mTOR pathway, leading to heightened B cell proliferation. Notably, B cells from MAPK4 KO mice produce significantly higher levels of IL-6, a key pro-inflammatory cytokine in RA. Furthermore, MAPK4 KO mice exhibit impaired T cell-independent humoral immune responses. Mechanistically, MAPK4 inhibits the activation of the PI3K signaling pathway in B cells by activating the IRF4-SHIP1 pathway. Treatment with the MAPK4 agonist Vacquinol-1 enhances MZ B cell differentiation in WT mice and reduces IL-6 secretion in CIA mouse models. In summary, this study reveals the diverse roles of MAPK4 in regulating of B cell functions, with potential implications for developing therapeutic strategies for RA and related autoimmune diseases. |
| format | Article |
| id | doaj-art-f64c0b861bb74a889324fd9968bd87ee |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-f64c0b861bb74a889324fd9968bd87ee2025-01-26T12:54:48ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111510.1038/s41419-025-07352-2MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathwayPei Huang0Guangli Yang1Pingping Zhang2Yin Zhu3Yaning Guan4Jian Sun5Qian Li6Yang An7Xiaoqi Shi8Juanjuan Zhao9Chaohong Liu10Zhixu He11Yan Chen12Zuochen Du13Department of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Immunology, Zunyi Medical UniversityDepartment of Pathogen Biology, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical UniversityAbstract The involvement of B lymphocytes in the pathogenesis of rheumatoid arthritis (RA) is well-established, with their early and aberrant activation being a crucial factor. However, the mechanisms underlying this abnormal activation in RA remain incompletely understood. In this study, we identified a significant reduction in MAPK4 expression in both RA patients and collagen-induced arthritis (CIA) mouse models, which correlates with disrupted B cell activation. Using MAPK4 knockout (KO) mice, we demonstrated that MAPK4 intrinsically promotes the differentiation of marginal zone (MZ) B cells. Loss of MAPK4 in KO mice enhances proximal BCR signaling and activates the PI3K-AKT-mTOR pathway, leading to heightened B cell proliferation. Notably, B cells from MAPK4 KO mice produce significantly higher levels of IL-6, a key pro-inflammatory cytokine in RA. Furthermore, MAPK4 KO mice exhibit impaired T cell-independent humoral immune responses. Mechanistically, MAPK4 inhibits the activation of the PI3K signaling pathway in B cells by activating the IRF4-SHIP1 pathway. Treatment with the MAPK4 agonist Vacquinol-1 enhances MZ B cell differentiation in WT mice and reduces IL-6 secretion in CIA mouse models. In summary, this study reveals the diverse roles of MAPK4 in regulating of B cell functions, with potential implications for developing therapeutic strategies for RA and related autoimmune diseases.https://doi.org/10.1038/s41419-025-07352-2 |
| spellingShingle | Pei Huang Guangli Yang Pingping Zhang Yin Zhu Yaning Guan Jian Sun Qian Li Yang An Xiaoqi Shi Juanjuan Zhao Chaohong Liu Zhixu He Yan Chen Zuochen Du MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway Cell Death and Disease |
| title | MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway |
| title_full | MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway |
| title_fullStr | MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway |
| title_full_unstemmed | MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway |
| title_short | MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway |
| title_sort | mapk4 inhibits the early aberrant activation of b cells in rheumatoid arthritis by promoting the irf4 ship1 signaling pathway |
| url | https://doi.org/10.1038/s41419-025-07352-2 |
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