2. Academic Validation
  3. CCL2 regulation of MST1-mTOR-STAT1 signaling axis controls BCR signaling and B-cell differentiation

CCL2 regulation of MST1-mTOR-STAT1 signaling axis controls BCR signaling and B-cell differentiation

  • Cell Death Differ. 2021 Sep;28(9):2616-2633. doi: 10.1038/s41418-021-00775-2.
Lu Yang 1,  Na Li 2,  Di Yang 3 4 5 6,  Anwei Chen 3 4 5 6 7,  Jianlong Tang 8,  Yukai Jing 1,  Danqing Kang 1,  Panpan Jiang 1,  Xin Dai 1,  Li Luo 1,  Qiuyue Chen 2,  Jiang Chang 1,  Ju Liu 1,  Heng Gu 1,  Yanmei Huang 1,  Qianglin Chen 2,  Zhenzhen Li 1,  Yingzi Zhu 9,  Heather Miller 10,  Yan Chen 11,  Liru Qiu 12,  Heng Mei 13,  Yu Hu 13,  Quan Gong 2,  Chaohong Liu 14
Affiliations

Affiliations

  • 1 Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China.
  • 3 Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Ministry of Education Key Laboratory of Child Development and Disorder, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 6 International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 7 Department of Dermatology, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 8 Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 10 Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
  • 11 The Second Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
  • 12 Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 13 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 14 Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
PMID: 33879857 DOI: 10.1038/s41418-021-00775-2
Abstract

Chemokines are important regulators of the immune system, inducing specific cellular responses by binding to receptors on immune cells. In SLE patients, decreased expression of CCL2 on mesenchymal stem cells (MSC) prevents inhibition of B-cell proliferation, causing the characteristic autoimmune phenotype. Nevertheless, the intrinsic role of CCL2 on B-cell autoimmunity is unknown. In this study using Ccl2 KO mice, we found that CCL2 deficiency enhanced BCR signaling by upregulating the phosphorylation of the MST1-mTORC1-STAT1 axis, which led to reduced marginal zone (MZ) B cells and increased germinal center (GC) B cells. The abnormal differentiation of MZ and GC B cells were rescued by in vivo inhibition of mTORC1. Additionally, the inhibition of MST1-mTORC1-STAT1 with specific inhibitors in vitro also rescued the BCR signaling upon antigenic stimulation. The deficiency of CCL2 also enhanced the early activation of B cells including B-cell spreading, clustering and signalosome recruitment by upregulating the DOCK8-WASP-actin axis. Our study has revealed the intrinsic role and underlying molecular mechanism of CCL2 in BCR signaling, B-cell differentiation, and humoral response.

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