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The sequential role of Mst1/mTORC1/STAT1 activity in chemokine receptor 2-regulated B cell receptor signaling
  • +18
  • Yingzi Zhu,
  • Heng Gu,
  • Lu Yang,
  • Na Li,
  • Qiuyue Chen,
  • Danqing Kang,
  • Yukai Jing,
  • Panpan Jiang,
  • Qianglin Chen,
  • Li Luo,
  • Ju Liu,
  • Jiang Chang,
  • Zhenzhen Li,
  • Yi Wang,
  • Xin Dai,
  • Heather Miller,
  • Lisa Westerberg,
  • Chan-Sik Park,
  • Masato Kubo,
  • Lingli Dong,
  • Chaohong Liu
Yingzi Zhu
Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Corresponding Author:[email protected]

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Heng Gu
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Lu Yang
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Na Li
Department of Oncology, First Affiliated Hospital of Yangtze University
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Qiuyue Chen
Department of Immunology, School of Medicine, Yangtze University
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Danqing Kang
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Yukai Jing
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Panpan Jiang
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Qianglin Chen
Department of Immunology, School of Medicine, Yangtze University
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Li Luo
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Ju Liu
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Jiang Chang
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Zhenzhen Li
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Yi Wang
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Xin Dai
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Heather Miller
Department of Research and Development, BD Biosciences
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Lisa Westerberg
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet
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Chan-Sik Park
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine
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Masato Kubo
Laboratory for Cytokine Regulation, Center for Integrative Medical Science (IMS), RIKEN Yokohama Institute
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Lingli Dong
Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
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Chaohong Liu
Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology
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Abstract

Background: Chemokine (C-C motif) receptor 2 (CCR2) contributes to autoimmune pathogenesis. However, the effect of CCR2 on B cell signaling and its role in autoimmunity remains unclear. Herein, we investigated the role of CCR2 in the B cell receptor (BCR) signaling pathway and aimed to illustrate its potential molecular mechanisms of action. Methods: To investigate the alterations in B cell signaling and the immune response, we used flow cytometry, western blotting, microscopic techniques, Seahorse assay, and immunofluorescence assay on samples from C57BL/6 mice and germinal CCR2-deletion mice. Results: The absence of CCR2 disturbed follicular B cell development. Furthermore, CCR2 absence was correlated with increased mTORC1-mediated energy metabolism and enhanced early B cell activation, which were induced by the up-regulation of BCR proximal signaling and F-actin accumulation. Mst1 and STAT1 were key factors in up-regulating the B cell activation in CCR2 deficient mice. The disrupted peripheral B cell differentiation and enhanced B cell signaling were associated with the inhibition mTORC1, Mst1, and STAT1. Moreover, loss of CCR2 caused a weakened T cell dependent antigen response, resulting in decreased antibody secreting cells and diminished antigen specific IgM levels. Conclusion: CCR2 is involved in the regulation of BCR signaling pathway by sequentially activating signaling pathways dominated by Mst1, mTORC1, and STAT1. Our study suggests that CCR2 might represent a novel therapeutic targeted for autoimmune diseases.