Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms. Issue 7 (19th August 2015)

• Record Type: Journal Article
• Authors: Connolly, Mary; Rooney, Peter R; McGarry, Trudy; Maratha, Ashwini X; McCormick, Jennifer; Miggin, Sinead M; Veale, Douglas J; Fearon, Ursula
• Is Part Of: Annals of the rheumatic diseases. Volume 75:Issue 7(2016)
• Page Start: 1392
• Page End: 1398
• Publication Date: 2015-08-19
• Subjects: Inflammation -- Rheumatoid Arthritis -- Fibroblasts; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2015-207655
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : 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.