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Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis

Author

Listed:
  • Wei-Dan Luo

    (Macau University of Science and Technology
    The Affiliated Hospital of Southwest Medical University, Southwest Medical University
    Macau University of Science and Technology)

  • Yu-Ping Wang

    (Macau University of Science and Technology
    Macau University of Science and Technology
    The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Southwest Medical University)

  • Jun Lv

    (The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Southwest Medical University)

  • Yong Liu

    (The Affiliated Hospital of Southwest Medical University, Southwest Medical University)

  • Yuan-Qing Qu

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Xiong-Fei Xu

    (Macau University of Science and Technology
    The Affiliated Hospital of Southwest Medical University, Southwest Medical University
    Macau University of Science and Technology)

  • Li-Jun Yang

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Zi-Cong Lin

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Lin-Na Wang

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Rui-Hong Chen

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Jiu-Jie Yang

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Ya-Ling Zeng

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Rui-Long Zhang

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Bai-Xiong Huang

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Xiao-Yun Yun

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Xuan-Ying Wang

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Lin-Lin Song

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Jian-Hui Wu

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Xing-Xia Wang

    (Macau University of Science and Technology
    The Affiliated Hospital of Southwest Medical University, Southwest Medical University
    Macau University of Science and Technology)

  • Xi Chen

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Wei Zhang

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Hui-Miao Wang

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Li-Qun Qu

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Meng-Han Liu

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Liang Liu

    (Macau University of Science and Technology)

  • Betty Yuen Kwan Law

    (Macau University of Science and Technology
    Macau University of Science and Technology)

  • Vincent Kam Wai Wong

    (Macau University of Science and Technology
    Macau University of Science and Technology)

Abstract

The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that the accumulation of DNA fragments, increasing with age and regulated by the exonuclease TREX1, promotes abnormal activation of the immune system in an adjuvant‐induced arthritis (AIA) rat model. Local overexpression of TREX1 suppresses synovial inflammation in rats, while conditional genomic deletion of TREX1 in AIA rats result in higher levels of circulating free (cf) DNA and hence abnormal immune activation, leading to more severe symptoms. The dysregulation of the heterodimeric transcription factor AP-1, formed by c-Jun and c-Fos, appear to regulate both TREX1 expression and SASP induction. Thus, our results confirm that DNA fragments are inflammatory mediators, and TREX1, downstream of AP-1, may serve as regulator of cellular immunity in health and in RA.

Suggested Citation

  • Wei-Dan Luo & Yu-Ping Wang & Jun Lv & Yong Liu & Yuan-Qing Qu & Xiong-Fei Xu & Li-Jun Yang & Zi-Cong Lin & Lin-Na Wang & Rui-Hong Chen & Jiu-Jie Yang & Ya-Ling Zeng & Rui-Long Zhang & Bai-Xiong Huang , 2023. "Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40113-3
    DOI: 10.1038/s41467-023-40113-3
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    Cited by:

    1. Samuel D. Chauvin & Shoichiro Ando & Joe A. Holley & Atsushi Sugie & Fang R. Zhao & Subhajit Poddar & Rei Kato & Cathrine A. Miner & Yohei Nitta & Siddharth R. Krishnamurthy & Rie Saito & Yue Ning & Y, 2024. "Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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