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The impact of exogenous and endogenous nucleic acids on the development of joint inflammation
Arthritis Res Ther volume 5, Article number: 111 (2003)
Chronic joint inflammation, as in the case of rheumatoid arthritis (RA), is characterized by an aseptic disease course. Nonetheless, free nucleic acids of bacterial origin are readily found in the inflamed synovial fluid of RA patients. The aim of the present study was to assess the potential of exogenous and endogenous nucleic acids to trigger joint inflammation in a healthy joint.
Materials and methods
Isolated and highly purified bacterial DNA, viral dsRNA, and endogenous mitochondrial (mt) and nuclear DNA, as well as synthetically produced homologues of these molecules, were all assessed for their in vitro and in vivo inflammatogenic potential. In addition, the intracellular pathways involved in the resulting inflammatory cascades were investigated.
Bacterial DNA-triggered inflammatory joint responses were primarily mediated by macrophages and their products (tumour necrosis factor). This inflammation was due to the cytidine phosphate guanosine content of DNA, which, as we have previously shown, promotes both macrophage and polymorphonuclear leukocyte activation and production of proinflammatory cytokines. Endogenous mtDNA but not nuclear DNA also gave rise to joint inflammation. However, in this case we have shown that the additional driving force for the inflammation is the oxidation status of the DNA. Importantly, mtDNA was readily detected in synovial fluid of a great majority of patients with RA. Finally, dsRNA of both synthetic and viral origin gave rise to joint inflammation, characterized by influx of both macrophages and T lymphocytes. In vitro, dsRNA induced NF-κB activation and production of chemokines and cytokines.
The capacities of endogenous and exogenous nucleic acids to promote joint inflammation depend on the occurrence of cytidine phosphate guanosine moieties, on the oxidation status of the DNA, and on the double stranded configuration of RNA. These finding indicate the regulation of inflammatory responses in the joint by specific interactions between certain exogenous as well as endogenous nucleic acids and host cells expressing Toll-like receptor 3 and Toll-like receptor 9.
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Tarkowski, A., Bjersing, J., Bokarewa, M. et al. The impact of exogenous and endogenous nucleic acids on the development of joint inflammation. Arthritis Res Ther 5 (Suppl 3), 111 (2003). https://doi.org/10.1186/ar912