Article Text


Triggering of viral RNA sensors induces CD55 expression on synovial fibroblasts
  1. O N Karpus1,
  2. K M Heutinck1,2,
  3. P J M Wijnker1,
  4. P P Tak3,
  5. J Hamann1
  1. 1Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
  2. 2Renal Transplant Unit, Academic Medical Center, Amsterdam, The Netherlands
  3. 3Division of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands


Background and objectives CD55 (decay-accelerating factor) is a complement-regulatory protein, which is highly expressed by fibroblast-like synoviocytes (FLS). CD55 is also a ligand for CD97, an adhesion-type G protein-coupled receptor abundantly present on leucocytes. We recently showed that lack of either CD55 or CD97 ameliorates disease in murine collagen-induced and K/BxN serum transfer models of arthritis.1 Little is known regarding the regulation of CD55 expression in FLS. We therefore investigated the effect of toll-like receptors ligation and pro-inflammatory cytokines on CD55 expression.

Materials and methods Synovial fibroblasts, obtained from biopsy samples of arthritis patients, were cultured and stimulated with cytokines (TNF, IFNγ, IL-1β, IL-6, IFNα) or TLR ligands (LTA, poly (I:C), LPS, imiquimod, CpG). Expression of CD55 was measured by flow cytometry using domain-specific monoclonal antibodies and recombinant CD97-loaded fluorescent beads. Chloroquine was used to inhibit TLR3 activity. Upregulation and functionality of dsRNA sensors in response to poly (I:C) or 5'-triphosphate RNA was analysed by PCR. Apoptosis was measured by PI/annexinV staining and was blocked with the pan-caspase inhibitor Q-VD-OPH.

Results Cultured synovial fibroblasts of patients with rheumatoid arthritis (RA), osteoarthritis, psoriatic arthritis, and spondylarthritis express equal amount of CD55. Stimulation of RA-FLS with IL-1β (p=0.02) and poly (I:C) (p=0.001) induced a significant upregulation of CD55. Engagement of TLR3 by the dsRNA analog poly (I:C) was confirmed using chloroquine, an inhibitor of endosomal acidification that impairs TLR3 signaling. Synovial fibroblasts also expressed the cytoplasmic dsRNA sensors melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). Stimulation of these receptors with either poly (I:C) or 5'-triphosphate RNA induced CD55 expression, but, in case of MDA5, also induced significant cell death (p<0.001) that was caspase-dependent. Upregulation of CD55 in response to dsRNA receptor activation increased the binding capacity of synovial fibroblasts for CD97-loaded beads.

Conclusions We identify dsRNA as a potent inducer of CD55 upregulation on synovial fibroblasts. Our findings suggest that CD55 induction by viral dsRNA or dsRNA may facilitate the accumulation of CD97-expressing inflammatory immune cells in the synovial tissue.

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