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P020 Toll-like receptor 9 influences inflammatory arthritis and osteoclastogenesis
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  1. A Fischer1,
  2. S Abdollahi-Rodsaz2,3,
  3. ACY Yau4,
  4. E Lonnblom4,
  5. R Holmdahl4,
  6. G Steiner1
  1. 1Division of Rheumtology, Internal Medicine III, Medical University of Vienna, Vienna, Austria
  2. 2Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
  3. 3Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, USA
  4. 4Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

Abstract

Introduction Release and insufficient removal of endogenous nucleic acids may be involved in triggering 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.

Objectives To gain more insight into the role of TLR9 in autoimmune arthritis, TLR9 inhibition was investigated in rats with pristane-induced arthritis (PIA). To further investigate TLR9 involvement, streptococcal cell wall (SCW) arthritis was induced in TLR9-/- mice.

Methods Arthritis was induced in mice with SCW lysates and in rats with the mineral oil pristane. Rats were treated with a TLR9 antagonist, starting before disease induction. Arthritis was scored using established scoring systems, inflammation and bone erosion was quantified by histological analysis of the paws. Levels of α−1-acid-glycoprotein (AGP), rheumatoid factor (RF) and IL-6 in sera were analysed. The role of TLR9 in osteoclast differentiation was investigated in vitro.

Results In PIA, which is T cell-dependent, the TLR9 antagonist reduced arthritis severity by ~50%. This was accompanied by a reduction of AGP, IL-6 and RF in the sera of these animals. In addition, TLR9 inhibition led to reduced inflammation, bone erosion and cartilage degradation in the paws. Moreover, the T cell-dependent chronic phase of SCW arthritis was significantly suppressed in TLR9-/- mice. Remarkably, TLR7 and TLR9 mRNA levels 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 The results suggest a crucial role for TLR9 in the T cell-dependent phases of PIA and SCW arthritis and thus an important involvement of the DNA (CpG) recognising TLR9 in the induction of arthritogenic autoimmune reactions. In addition, TLR9 also seems to play a role in the initiation of osteoclast differentiation which needs to be further elucidated in future experiments.

Disclosure of interest None declared

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