loading page

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

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.