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- Volume 81,Issue 11
- Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways
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Rheumatoid arthritis
Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways
- Yi Qin1,
- Ming-Long Cai1,
- Hui-Zhi Jin1,
- Wei Huang2,
- Chen Zhu2,
- http://orcid.org/0000-0001-8174-2118Aline Bozec3,
- Jingang Huang4,
- http://orcid.org/0000-0003-0828-1583Zhu Chen1
- 1Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- 2Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- 3Department of Internal Medicine III, Institute for Clinical Immunology University of Erlangen-Nuremberg, Erlangen, Germany
- 4Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Correspondence to Professor Zhu Chen, Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; doczchen{at}ustc.edu.cn
Abstract
Objectives Age-associated B cells (ABCs) are a recently identified B cell subset, whose expansion has been increasingly linked to the pathogenesis of autoimmune disorders. This study aimed to investigate whether ABCs are involved in the pathogenesis and underlying mechanisms of rheumatoid arthritis (RA).
Methods ABCs were assessed in collagen-induced arthritis (CIA) mice and patients with RA using flow cytometry. Transcriptomic features of RA ABCs were explored using RNA-seq. Primary fibroblast-like synoviocytes (FLS) derived from the synovial tissue of patients with RA were cocultured with ABCs or ABCs-conditioned medium (ABCsCM). IL-6, MMP-1, MMP-3 and MMP-13 levels in the coculture supernatant were detected by ELISA. Signalling pathways related to ABCs-induced FLS activation were examined using western blotting.
Results Increased ABCs levels in the blood, spleen and inflammatory joints of CIA mice were observed. Notably, ABCs were elevated in the blood, synovial fluid and synovial tissue of patients with RA and positively correlated with disease activity. RNA-seq revealed upregulated chemotaxis-related genes in RA ABCs compared with those in naive and memory B cells. Coculture of FLS with RA ABCs or ABCsCM led to an active phenotype of FLS, with increased production of IL-6, MMP-1, MMP-3 and MMP-13. Mechanistically, ABCsCM-derived TNF-α promoted the upregulation of interferon-stimulated genes in FLS, with elevated phosphorylation of ERK1/2 and STAT1. Furthermore, blockage of ERK1/2 and Janus Kinase (JAK)-STAT1 pathways inhibited the activation of FLS induced by ABCsCM.
Conclusions Our results suggest that ABCs contribute to the pathogenesis of RA by inducing the activation of FLS via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways.
- arthritis, rheumatoid
- B-Lymphocytes
- synovitis
- fibroblasts
Data availability statement
Data are available on reasonable request. The data supporting the results of this study are available from the corresponding author on reasonable request. The annotated genome and raw sequence reads were deposited at NCBI under Bioproject accession number PRJNA822860.
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- arthritis, rheumatoid
- B-Lymphocytes
- synovitis
- fibroblasts
Data availability statement
Data are available on reasonable request. The data supporting the results of this study are available from the corresponding author on reasonable request. The annotated genome and raw sequence reads were deposited at NCBI under Bioproject accession number PRJNA822860.
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Footnotes
Handling editor Josef S Smolen
YQ and M-LC contributed equally.
JH and ZC contributed equally.
Contributors YQ and M-LC performed the experiments, analysed the data and developed the figures. H-ZJ, WH and CZ collected the samples and analyzed the data. AB analysed the data and revised the manuscript. JH and ZC designed the study, analysed the data, wrote the manuscript and funded the study. ZC is responsible for the overall content as the guarantor.
Funding This work was supported by the National Natural Science Foundation of China (Grant No. 81 871 227 to ZC) and Anhui Provincial Key Research and Development Plan (No. 2022h11020009 to ZC).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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