ANTAGONIZING ENDOSOMAL TOLL-LIKE RECEPTORS DIMINISHES INFLAMMATORY ARTHRITIS

Background: Rheumatoid arthritis (RA), the most common chronic inflammatory joint disease, has a definite autoimmune background. There is evidence that release of endogenous nucleic acids triggers autoimmune reactions important for the onset of RA. In recent years, endosomal Toll-like receptors (TLRs, i.e. TLR3, TLR7, TLR8 and TLR9) have been implicated in autoimmune processes due to their ability to recognize these nucleic acids. Objectives: We study the role of TLR7 and TLR9 in the pathogenesis of arthritis by antagonizing them in the pristane-induced arthritis (PIA) model in DA rats. Methods: Different immunoregulatory sequences (IRS) known to inhibit TLR7/9-activity were tested in cultured rat splenocytes. Using the PIA model, these IRS were also tested for their efficiency in inhibiting arthritis development compared to placebo animals. The IRS' were applied twice a week subcutaneously at the base of the tail. Arthritis score and weight changes were assessed during the experiment. Paws, lymph nodes and spleen were taken for further protein-, RNA- and histological analysis. Furthermore, the impact of the IRS' was analyzed in an in vitro osteoclast formation assay using murine bone marrow-derived macrophages. Results: IRS against TLR7, TLR9 and TLR7/9 displayed a dose-dependent inhibition of pre-activated rat splenocytes. Interestingly, the combined TLR7/9 inhibitor did not diminish arthritis severity. However, antagonizing TLR9 alone led to reduced arthritis severity, which was also confirmed by diminished protein expression levels in paws and lymph nodes compared to the placebo group and the TLR7 inhibition therapy group. Moreover, bone destruction was strongly reduced in paws of rats treated with the TLR9-antagonist, as revealed by histological analysis of bone erosion, inflammation and number of osteoclasts of paws. Furthermore, in an in vitro osteoclast formation assay it could be shown that treatment with the combined TLR7/9 inhibitor and the TLR9 antagonist led to reduced osteoclastogenesis. Conclusions: We could show that DNA plays an important role in a rat model of inflammatory arthritis. Despite its role in the PIA rat model, DNA might also play an important role in the pathogenesis of human RA and antagonizing TLR9 might become a useful therapeutic option for RA. Disclosure of Interest: None DeclaredCitation: Annals of the Rheumatic Diseases, volume 71, supplement 3, year 2012, page 317Session: Innate immunity in rheumatic diseases (Poster Presentations )