Arthritogenecity of RNA and its degradation products

Sammanfattning: Viral infections often lead to arthralgias and overt arthritic states. Expression of double stranded RNA (dsRNA) is a common feature of all viruses during their replication and it has been suggested that it is able to induce production of pro-inflammatory cytokines, e.g., interferon-alpha (IFN-alpha). The aims of this thesis were to investigate i) whether dsRNA induces arthritis, ii) the role of IFN-alpha regarding the onset of joint inflammation induced by viral dsRNA iii) the impact of dsRNA and single stranded RNA (ssRNA) on the production of proteins belonging to fibrinolytic and coagulation cascades and iiii) the impact of soluble uric acid on the in vivo inflammatory responses including development of dsRNA-triggered arthritis. Histological signs of arthritis were evident already on day three following intra-articular administration of dsRNA and IFN-a whereas ssRNA was not able to induce arthritis. Arthritis was characterized by infiltration of macrophages into synovial tissue. It was not dependent on acquired immune responses since SCID mice being deficient for T- and B-lymphocytes also developed arthritis. Although dsRNA is a ligand for TLR3 and intracellular PKR, TLR3KO and PKRKO mice developed arthritis indicating that some other receptors are instrumental in the induction of inflammation. Importantly, we found that dsRNA arthritis was triggered through IL-1R- and IFNalpha/beta-receptor-signalling since mice being deficient for these molecules were unable to raise joint inflammation. Furthermore, pro-inflammatory cytokines and chemokines including TNF-alpha, IFN-alpha, IL-6, MCP-1, MIP-1alpha and the transcription factor, NF-kappaB were readily triggered in response to stimulation of mouse splenocytes with dsRNA. In addition, we assessed the impact of RNA on coagulation and fibrinolytic cascades. DsRNA efficiently and dose-dependently induced the expression of plasminogen whereas tissue factor was induced only by certain ssRNA. It is well-known that uric acid crystals, the naturally occurring degradation product of purine metabolism, a danger signal driving maturation of dendritic cells, display potent pro-inflammatory properties, being the cause of gout. In contrast, the biological properties of soluble uric acid are less well documented. Frequency and severity of dsRNA-induced arthritis, granulocyte-mediated inflammatory response and vasodilatation capacity were significantly decreased in mice treated systemically with soluble uric acid as compared to the control group. The data suggest that uric acid displays potent distant anti-inflammatory effects in vivo. This property seems to be mediated by down-regulation of neutrophil influx to the site of inflammatory insult by localized chemotactic effect of uric acid. Collectively, these findings demonstrate that there is a link between joint inflammation and viral infection since viral dsRNA, by its capacity to induce production of IFN-alpha, is clearly arthritogenic. The end product of RNA, uric acid is able to maintain a balance in the body by modulation of the inflammatory responses.