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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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
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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| Summary: | 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. |
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| ISSN: | 2041-4889 |