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OP0194 Involvement of toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis and during osteoclastogenesis
  1. A Fischer,
  2. B Meyer,
  3. B Niederreiter,
  4. G Steiner
  1. Internal Medicine III-Rheumatology, Medical University Vienna, Vienna, Austria

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, particularly in systemic lupus erythematosus, but their role in RA is less clear. Results previously obtained in rats with pristane-induced arthrits (PIA) suggested involvement of TLR9 in the pathogenesis of this arthritis model (1). Interestingly, rats with PIA develop autoantibodies associated with RA including rheumatoid factor, anti-RA33 and antibodies to carbamylated proteins (2).

Objectives To gain more insight into the role of TLR9 in the pathogenesis of autoimmune arthritis by investigating the effects of TLR9 inhibition in rats with PIA.

Methods Arthritis was induced in DA rats with the mineral oil pristane. Rats were treated with a TLR9 antagonist every other day, starting one before disease induction. Arthritis was scored using established scoring systems, inflammation and bone erosion were quantified by histological analysis. Expression of TLR9 and other nucleic acid sensing TLRs was quantified by RT-PCR and Western blotting; activation (phosphorylation) of various signal transduction molecules was determined by Western blotting. Furthermore, the role of TLR9 in osteoclast differentiation and activation was investigated in vitro.

Results The TLR9 antagonist significantly reduced clinical signs of arthritis by approximately 50%. Histological analyses revealed diminshed inflammation, cartilage degradation, bone erosion and significantly reduced numbers of osteoclasts in animals treated with the TLR9 antagonist. However, when treatment was started after onset of arthritis TLR9 inhibition had no effect on arthritis development and severity. IL-6 serum levels were greatly diminished in animals treated with the TLR9 antagonist and expression and activation of NF-kB in lymph nodes was reduced. 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 an important role for TLR9 in the T cell-dependent initiation phase of PIA and thus important involvement of endogenous DNA released during apoptosis, necrosis or netosis in the initiation of autoimmune arthritis and during osteoclastogenesis. The possible relevance of these findings for human RA needs to be further elucidated in future experiments.

References

  1. Hoffmann MH, Skriner K, Herman S, Baumann C, Steiner CW, Ospelt C, Meyer B, Gleiss A, Pfatschbacher J, Niederreiter B, Tuncel J, Zanoni G, Steiner G. Nucleic acid-stimulated antigen presenting cells trigger T cells to induce disease in a rat transfer model of inflammatory arthritis. J Autoimmun. 2011; 36:288–300.

  2. Stoop JN, Fischer A, Hayer S, Hegen M, Huizinga TW, Steiner G, Trouw LA, Toes RE. Anticarbamylated protein antibodies can be detected in animal models of arthritis that require active involvement of the adaptive immune system.Ann Rheum Dis. 2015; 74(5):949–50.

References

Disclosure of Interest None declared

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