Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis
Wei Luo, Yuping Wang, Jun Lü, Yongxin Liu, Yuan Qing Qu, Xiongfei Xu, Lijun Yang, Zicong Lin, Linna Wang, Ruihong Chen, Jiujie Yang, Yaling Zeng, Ruilong Zhang, Baixiong Huang, Xiaoyun Yun, Xuanying Wang, Linlin Song, Jianhui Wu, Xingxia Wang, Xi Chen, Wei Zhang, Hui-Miao Wang, Liqun Qu, Meng‐Han Liu, Liang Liu, Betty Yuen Kwan Law, Vincent Kam Wai Wong
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.