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β1 integrin mediates toll-like receptor 2 induced migration and invasion via rac1 activation
  1. T McGarry,
  2. M Connolly,
  3. J McCormick,
  4. W Gao,
  5. D J Veale,
  6. U Fearon
  1. Dublin Academic Medical Centre, University College Dublin, Dublin, Ireland


Background and objectives Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by synovial inflammation and destruction of cartilage and bone. TLR-2 is implicated in the pathogenesis of RA. This study investigates if TLR-2 induced cell migration and invasion is mediated through β1-integrin signalling pathways and cytoskeletal dynamics.

Materials and methods IA patients (n=20) underwent clinical assessment, video-arthroscopy and synovial biopsy pre/postbiologic therapy. Macroscopic synovitis/vascularity was measured by visual analogue scale.Immunohistology/immunoflourescence examined β1 integrin and filamentous actin (F-actin) expression in synovial tissue (ST), primary RA synovial fibroblasts (RASFC) and microvascular endothelial cells (MVEC). Cytoskeletal rearrangement following Pam3CSK4 (1ug/ml) (TLR-2-ligand) stimulation was examined by F-actin immunofluorescent staining. Pam3CSK4 induced adhesion, cell migration and invasion was assessed by FACS analysis, wound repair assays and transwell matrigel invasion chambers in the presence or absence of anti-β1 integrin (10 µg/ml) or IgG control antibody (10 µg/ml). Rac1 was assessed by immunoprecipitation and western blotting.

Results β1 integrin was highly expressed in IA ST compared to osteoarthritis and control tissue. β1 integrin lining and sublining layer expression significantly correlated with macroscopic synovitis (p<0.05), vascularity (p<0.05), and was significantly reduced in biologic responders. β1-integrin and F-actin expression predominantly co-localised to synovial blood vessels and lining layer. Pam3CSK4 induced cell surface expression of ICAM (p<0.05). Using RASFC and HDEC, Pam3CSK4 induced cell migration and cytoskeletal disassembly, resulting in filopodia and microspike formation and significantly induced Rac1 activation and cell invasion through a matrigel (p<0.05). Finally, the authors demonstrated that Pam3CSK4 induced cell migration was inhibited in the presence of anti- β1 integrin, an effect that was also observed for Pam3CSK4 induced cellular invasion and Rac1 activation (p<0.05). No effect was observed for IgG matched control antibody.

Conclusion β1-integrin is highly expressed in the inflamed joint and mediates cell TLR-2 induced migrational and invasive mechanisms, critical to the pathogenesis of IA.

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