Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms.

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.

• Authors: Mary Connolly, Peter R Rooney, Trudy McGarry, Ashwini X Maratha, Jennifer McCormick, Sinead M Miggin, Douglas J Veale, Ursula Fearon
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 75 Issue 7 Pg. 1392-8 (07 2016) ISSN: 1468-2060 [Electronic] England
• PMID: 26290589 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Chemical References

• Cytokines
• Ligands
• NF-kappa B
• Serum Amyloid A Protein
• Toll-Like Receptor 2
• Intercellular Adhesion Molecule-1

Topics

• Acute Disease
• Arthritis, Rheumatoid (blood, pathology)
• Cell Movement
• Cytokines (blood)
• Humans
• Intercellular Adhesion Molecule-1 (metabolism)
• Ligands
• NF-kappa B (metabolism)
• Neovascularization, Pathologic
• Serum Amyloid A Protein (metabolism)
• Toll-Like Receptor 2 (blood)