08.27 Impact of toll-like receptor 9 in inflammatory arthritis and osteoclastogenesis

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Abstract

Background

Release and insufficient removal of endogenous nucleic acids may be involved in triggering harmful autoimmune reactions important in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). Nucleic acid sensing molecules, such as the endosomal Toll-like receptors (TLRs) 7 and 9, have been linked to pathogenic autoimmune processes, but their role in RA is less clear.

Background

To gain more insight into the role of TLR9 in autoimmune arthritis, rats with pristane-induced arthritis (PIA) were treated with a TLR9 antagonist. To further investigate TLR9 involvement, serum transfer arthritis was induced in TLR9 knock-out mice.

Materials and methods

Arthritis was induced in mice with arthritogenic K/BxN serum and in rats with the mineral oil pristane. Rats were treated with a TLR9 antagonist every other day, starting one day before disease induction. Arthritis was scored using established scoring systems, inflammation and bone erosion were quantified by histological analysis. Furthermore, the role of TLR9 in osteoclast differentiation and activation was investigated in vitro.

Results

In the serum transfer model, which is independent of the adaptive immune system, arthritis severity was not changed in mice lacking a functional tlr9 gene. In PIA, which is T cell-dependent, the TLR9 antagonist reduced arthritis severity by ~50%. TLR9 inhibition led to reduced inflammation, bone erosion and cartilage degradation. However, when treatment was started after the onset of arthritis TLR9 inhibition did not influence disease severity. Treatment with the TLR9 antagonist influenced downstream signalling, mainly via NFκBp65, in lymph nodes. Remarkably, mRNA levels of TLR7 and TLR9 strongly differed in the course of in vitro osteoclastogenesis. Whereas TLR7 expression did not change throughout osteoclastogenesis, expression of TLR9 was higher in precursor cells than in mature osteoclasts and stimulation with a TLR9 agonist (CpG) completely inhibited osteoclastogenesis.

Conclusions

Taken together, the results suggest a role for TLR9 in the T cell-dependent initiation phase of PIA and thus an important involvement of the DNA (CpG) recognising TLR9 in the initiation of autoimmune arthritis and during osteoclastogenesis. The precise role(s) of TLR9 in the different stages of arthritis needs to be further elucidated in future experiments.

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