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


    Connolly, Mary and Rooney, Peter R and McGarry, Trudy and Maratha, Ashwini and McCormick, Jennifer and Miggin, Sinead and Veale, Douglas J and Fearon, Urusla (2016) Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms. Annals of the Rheumatic Diseases, 75. pp. 1392-1398. ISSN 0003-4967

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    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-SAAinduced 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 ASAA/TLR2 interaction may be a potential therapeutic intervention in RA.

    Item Type: Article
    Keywords: Acute; serum; amyloid A; TLR2; ligand; inflammatory; angiogenic mechanisms;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 12607
    Identification Number: https://doi.org/10.1136/annrheumdis-2015-207655
    Depositing User: Sinead Miggin
    Date Deposited: 25 Mar 2020 10:30
    Journal or Publication Title: Annals of the Rheumatic Diseases
    Publisher: BMJ Publishing Group
    Refereed: Yes
    URI:

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