Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis.
Wei-Dan LuoYu-Ping WangJun LvYong LiuYuan-Qing QuXiong-Fei XuLi-Jun YangZi-Cong LinLin-Na WangRui-Hong ChenJiu-Jie YangYa-Ling ZengRui-Long ZhangBai-Xiong HuangXiao-Yun YunXuan-Ying WangLin-Lin SongJian-Hui WuXing-Xia WangXi ChenWei ZhangHui-Miao WangLi-Qun QuMeng-Han LiuLiang LiuBetty Yuen Kwan LawVincent Kam Wai WongPublished in: Nature communications (2023)
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.
Keyphrases
- rheumatoid arthritis
- circulating tumor
- transcription factor
- cell free
- single molecule
- disease activity
- interstitial lung disease
- ankylosing spondylitis
- healthcare
- nucleic acid
- public health
- endothelial cells
- oxidative stress
- early stage
- circulating tumor cells
- poor prognosis
- risk factors
- gene expression
- health information
- risk assessment
- physical activity
- long non coding rna
- genome wide