Background and Objectives There is some evidence that release and insufficient removal of endogenous nucleic acids may be involved in triggering harmful autoimmune reactions that might be important in the initiation of RA. Nucleic acid-sensing molecules, such as the endosomal Toll-like receptors (TLRs) 7 and 9, have been linked to pathogenic autoimmune processes, particularly in SLE, but their role in RA is less clear. Data recently obtained in rats with pristane-induced arthritis (PIA) suggested involvement of TLR9, because antagonizing this receptor in the initiation phase of the disease led to an improved clinical outcome of arthritis.
To gain more insight into the role of TLR9 in autoimmune arthritis we have extended our studies to the K/BxN serum-transfer arthritis model which is reflecting the effector phase of erosive autoimmune arthritis.
Materials and Methods Arthritis was induced in C57BL/6 mice by two subsequent injections of arthritogenic serum. Antagonists for TLR7 and TLR9 or an agonist for TLR9, respectively, a non-inhibitory control sequence or PBS as placebo was applied every third day. The first treatment was given one day before disease induction. To further investigate TLR9 involvement, arthritis was also induced in TLR9 knock-out mice. Furthermore, the effect of TLR9 on osteoclast differentiation and activation was investigated in an in vitro osteoclast formation assay.
Results Neither inhibitor affected arthritis onset and severity in the serum transfer model, which is independent of the adaptive immune system, in contrast to PIA. Furthermore, arthritis severity was not changed in mice lacking a functional tlr9 gene in comparison to wild type animals. In contrast, treatment with a TLR9 agonist led to an improved clinical outcome.
Remarkably, in vitro formation of osteoclasts appeared to be slightly enhanced in cells isolated from TLR9-/- mice compared to those from wild type animals. Moreover, osteoclastogenesis was reduced by ~60% in cells from wild type animals grown in the presence of the TLR9 agonist whereas, as expected, no effect was seen in cells from TLR9-/- animals.
Conclusions These results suggest that TLR9 might play a beneficial regulatory role in the effector phase of erosive autoimmune arthritis by negatively affecting differentiation and activation of bone resorbing osteoclasts. Nevertheless, the precise role of TLR9 in the different stages of arthritis needs to be further elucidated.
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