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  3. MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway

MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway

  • Cell Death Dis. 2025 Jan 26;16(1):43. doi: 10.1038/s41419-025-07352-2.
Pei Huang # 1 2 3,  Guangli Yang # 1 2 3,  Pingping Zhang # 1 2 3,  Yin Zhu 1 2 3,  Yaning Guan 1 2 3,  Jian Sun 1 2 3,  Qian Li 1 2 3,  Yang An 1 2 3,  Xiaoqi Shi 1 2 3,  Juanjuan Zhao 4,  Chaohong Liu 5,  Zhixu He 6 7 8,  Yan Chen 9 10 11,  Zuochen Du 12 13 14
Affiliations

Affiliations

  • 1 Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
  • 2 Guizhou Children's Hospital, Zunyi, China.
  • 3 Collaborative Innovation Center for Tissue Injury Repair and Regenerative Medicine of Zunyi Medical University, Zunyi, China.
  • 4 Department of Immunology, Zunyi Medical University, Zunyi, China.
  • 5 Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China. 1179909832@qq.com.
  • 7 Guizhou Children's Hospital, Zunyi, China. 1179909832@qq.com.
  • 8 Collaborative Innovation Center for Tissue Injury Repair and Regenerative Medicine of Zunyi Medical University, Zunyi, China. 1179909832@qq.com.
  • 9 Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China. cyz600@163.com.
  • 10 Guizhou Children's Hospital, Zunyi, China. cyz600@163.com.
  • 11 Collaborative Innovation Center for Tissue Injury Repair and Regenerative Medicine of Zunyi Medical University, Zunyi, China. cyz600@163.com.
  • 12 Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China. dzc9036@126.com.
  • 13 Guizhou Children's Hospital, Zunyi, China. dzc9036@126.com.
  • 14 Collaborative Innovation Center for Tissue Injury Repair and Regenerative Medicine of Zunyi Medical University, Zunyi, China. dzc9036@126.com.
  • # Contributed equally.
PMID: 39863600 DOI: 10.1038/s41419-025-07352-2
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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