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Extended report
Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms
  1. Mary Connolly1,
  2. Peter R Rooney1,
  3. Trudy McGarry1,
  4. Ashwini X Maratha2,
  5. Jennifer McCormick1,
  6. Sinead M Miggin2,
  7. Douglas J Veale1,
  8. Ursula Fearon1
  1. 1Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre and Conway Institute of Biomolecular and Biomedical Research, Dublin 4, Ireland
  2. 2Department of Biology, Institute of Immunology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland
  1. Correspondence to Dr Ursula Fearon, Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, St. Vincent's University Hospital, Dublin 4, Ireland; ursula.fearon{at}


Introduction Acute-phase serum amyloid A (A-SAA) has cytokine-like properties and is expressed at sites of inflammation. We examined whether A-SAA-induced pro-inflammatory mechanisms are mediated through Toll-like receptor 2 (TLR2) in rheumatoid arthritis (RA).

Methods The effect of A-SAA on human embryonic kidney (HEK), TLR2 or TLR4 cells was quantified by nuclear factor (NF)-κB luciferase reporter assays. A-SAA-induced RASFC and dHMVEC function were performed in the presence of a specific neutralising anti-TLR2 mAb (OPN301) (1 μg/mL) and matched IgG isotype control Ab (1 μg/mL). Cell surface expression of intracellular adhesion molecule (ICAM)-1, chemokine expression, cell migration, invasion and angiogenesis were assessed by flow cytometry, ELISA, Matrigel invasion chambers and tube formation assays. MyD88 expression was assessed by real-time PCR and western blot.

Results A-SAA induced TLR2 activation through induction of NF-κB (p<0.05), but failed to induce NF-κB in HEK-TLR4 cells, confirming specificity for TLR2. A-SAA-induced proliferation, invasion and migration were significantly inhibited in the presence of anti-TLR2 (all p<0.05), with no significant effect observed for tumour necrosis factor-α-induced events. Additionally, A-SAA-induced ICAM-1, interleukin-8, monocyte chemoattractant protein-1, RANTES and GRO-α expression were significantly reduced in the presence of anti-TLR2 (all p<0.05), as was A-SAA induced angiogenesis (p<0.05). Finally, A-SAA induced MyD88 signalling in RASFC and dHMVEC (p<0.05).

Conclusions A-SAA is an endogenous ligand for TLR2, inducing pro-inflammatory effects in RA. Blocking the A-SAA/TLR2 interaction may be a potential therapeutic intervention in RA.

  • Inflammation
  • Rheumatoid Arthritis
  • Fibroblasts

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