AB0040 Toll-like receptor 9 influences inflammatory arthritis and osteoclastogenesis. (12th June 2018)

• Record Type: Journal Article
• Authors: Fischer, A.; Abdollahi-Rodsaz, S.; Yau, A.C.Y.; Lönnblom, E.; Meyer, B.; Niederreiter, B.; Holmdahl, R.; Steiner, G.
• Is Part Of: Annals of the rheumatic diseases. Volume 77(2018)Supplement 2
• Page Start: 1220
• Page End: 1220
• Publication Date: 2018-06-12
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-eular.4557
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: 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. Data obtained in rats with pristane-induced arthritis (PIA) suggested involvement of TLR9 in the pathogenesis of this arthritis model 1 . Objectives: To gain more insight into the role of TLR9 in autoimmune arthritis, TLR9 inhibition with specific oligodeoxynucleotide sequences (ODN) 2 was investigated in rats with 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 were quantified by histological analysis. Levels of α−1-acid-glycoprotein (AGP), rheumatoid factor (RF) and IL-6 in sera were analysed. The role of TLR9 in osteoclast differentiation and activation was investigated in vitro . Results: In PIA, the TLR9 antagonist reduced arthritis severity by ~50%, which was accompanied by a reduction of AGP, IL-6 and RF. TLR9 inhibition led to reduced inflammation, bone erosion and cartilage degradation. 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: Taken together, the results suggest a role for TLR9 in the T cell-dependent phases of PIA and SCW arthritis 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. References: [1] Hoffmann MH, et al. Nucleic acid-stimulated antigen-presenting cells trigger T cells to induce disease in a rat transfer model of inflammatory arthritis. J Autoimmun, 2011;36(3–4):288–300. [2] Duramad O, et al. Inhibitors of TLR-9 act on multiple cell subsets in mouse and man in vitro and prevent death in vivo from systemic inflammation. J Immunol, 2005;174(9):5193–200. Disclosure of Interest: None declared