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

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, Xiao-Yun Yun, Xuan-Ying Wang, Lin-Lin Song, Jian-Hui Wu, Xing-Xia Wang, Xi Chen, Wei Zhang, Hui-Miao Wang, Li-Qun Qu, Meng-Han Liu, Liang Liu (), Betty Yuen Kwan Law () and Vincent Kam Wai Wong ()
Additional contact information
Wei-Dan Luo: Macau University of Science and Technology
Yu-Ping Wang: Macau University of Science and Technology
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
Xiong-Fei Xu: Macau University of Science and Technology
Li-Jun Yang: Macau University of Science and Technology
Zi-Cong Lin: Macau University of Science and Technology
Lin-Na Wang: Macau University of Science and Technology
Rui-Hong Chen: Macau University of Science and Technology
Jiu-Jie Yang: Macau University of Science and Technology
Ya-Ling Zeng: Macau University of Science and Technology
Rui-Long Zhang: Macau University of Science and Technology
Bai-Xiong Huang: Macau University of Science and Technology
Xiao-Yun Yun: Macau University of Science and Technology
Xuan-Ying Wang: Macau University of Science and Technology
Lin-Lin Song: Macau University of Science and Technology
Jian-Hui Wu: Macau University of Science and Technology
Xing-Xia Wang: Macau University of Science and Technology
Xi Chen: Macau University of Science and Technology
Wei Zhang: Macau University of Science and Technology
Hui-Miao Wang: Macau University of Science and Technology
Li-Qun Qu: Macau University of Science and Technology
Meng-Han Liu: Macau University of Science and Technology
Liang Liu: Macau University of Science and Technology
Betty Yuen Kwan Law: Macau University of Science and Technology
Vincent Kam Wai Wong: Macau University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40113-3

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