Self-DNA accumulation as a risk factor for accelerating the pathogenesis of rheumatoid arthritis in elderly individuals

Ageing is an unavoidable process in humans and a major factor for the increasing risk of various diseases. In the United States, more than 50% of rheumatoid arthritis patients are middle-aged or elderly, but the risk factors and mechanisms by which ageing increases the incidence of rheumatoid arthritis are not known. It has been suggested that the accumulation of DNA fragments increases the risk of autoimmune diseases, such as systemic lupus erythematosus. DNA fragments are a common nucleic acid metabolite in ageing organisms as well as in the serum of humans and animals with rheumatoid arthritis; therefore, we hypothesize that DNA fragments are one of the factors contributing to the development of rheumatoid arthritis due to ageing. First, we analysed two in vitro DNA damage response models by using a gene silencing approach and determined that the DNA fragment clearance gene TREX1 can regulate inflammatory factor release in normal cells. Second, after TREX1 expression was knocked down locally or systemically in rats via the Cre-LoxP system and compared with that in AIA(adjuvant-induced arthritis) model rats treated with AAV-TREX1, it was determined that DNA fragments can result in manifestations of arthritis and abnormal activation of the immune system in rats. These results, including the low expression of the TREX1 gene in clinical patient and AIA model samples and the results of immunohistochemical, Western blot, and transcriptome analyses, revealed that the TREX1 gene can regulate cellular senescence-associated secretory phenotype (SASP)-related manifestations and showed that dysregulation of c-Jun and c-Fos, components of the TREX1 transcription factor AP-1, is associated with SASP induction. Finally, it was confirmed in vitro that different causes of decreased c-Fos expression can inhibit TREX1 expression. These DNA fragments are potent producers of inflammation-releasing mediators, and TREX1 is an effective degrader of DNA fragments; it is also a key gene that regulates cellular immunity and ageing. Therefore, effectively clearing excess DNA fragments from the body and ensuring the health of senescent cells may be a potential prevention strategy for RA.