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- Title
Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis.
- Authors
Luo, Wei-Dan; Wang, Yu-Ping; Lv, Jun; Liu, Yong; Qu, Yuan-Qing; Xu, Xiong-Fei; Yang, Li-Jun; Lin, Zi-Cong; Wang, Lin-Na; Chen, Rui-Hong; Yang, Jiu-Jie; Zeng, Ya-Ling; Zhang, Rui-Long; Huang, Bai-Xiong; Yun, Xiao-Yun; Wang, Xuan-Ying; Song, Lin-Lin; Wu, Jian-Hui; Wang, Xing-Xia; Chen, Xi
- 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. The incidence of rheumatoid arthritis (RA) and accumulation of circulating free (cf) DNA increase with age but it is unknown whether DNA fragments cause joint inflammation. Here authors show that cf DNA levels are higher in RA patients and that in a rat adjuvant-induced arthritis model, the exonuclease TREX1 suppresses synovial inflammation via promoting the degradation of cf DNA and inhibiting a senescence-like cellular state.
- Subjects
RHEUMATOID arthritis; CELLULAR aging; AP-1 transcription factor; IMMUNOSENESCENCE; ADJUVANT arthritis; INFLAMMATORY mediators; ARTHRITIS; CIRCULATING tumor DNA
- Publication
Nature Communications, 2023, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40113-3