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Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants
  1. Linda M Hartkamp1,2,
  2. Jay S Fine3,
  3. Inge E van Es1,2,
  4. Man Wai Tang1,2,
  5. Michael Smith3,
  6. John Woods3,
  7. Satwant Narula3,
  8. Julie DeMartino3,
  9. Paul P Tak2,4,
  10. Kris A Reedquist1,2
  1. 1Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  3. 3Department of Inflammation Discovery, Hoffmann-La Roche, Inc., Nutley, New Jersey, USA
  4. 4GlaxoSmithKline, Stevenage, and University of Cambridge, Cambridge, UK
  1. Correspondence to Dr Kris A Reedquist, Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Room K0–138, Meibergdreef 9, Amsterdam AZ 1105, The Netherlands; k.a.reedquist{at}amc.uva.nl

Abstract

Objectives Bruton's tyrosine kinase (Btk) is required for B lymphocyte and myeloid cell contributions to pathology in murine models of arthritis. Here, we examined the potential contributions of synovial Btk expression and activation to inflammation in rheumatoid arthritis (RA).

Materials and methods Btk was detected by immunohistochemistry and digital image analysis in synovial tissue from biologically naive RA (n=16) and psoriatic arthritis (PsA) (n=12) patients. Cell populations expressing Btk were identified by immunofluorescent double labelling confocal microscopy, quantitative (q-) PCR and immunoblotting. The effects of a Btk-specific inhibitor, RN486, on gene expression in human macrophages and RA synovial tissue explants (n=8) were assessed by qPCR, ELISA and single-plex assays.

Results Btk was expressed at equivalent levels in RA and PsA synovial tissue, restricted to B lymphocytes, monocytes, macrophages and mast cells. RN486 significantly inhibited macrophage IL-6 production induced by Fc receptor and CD40 ligation. RN486 also reduced mRNA expression of overlapping gene sets induced by IgG, CD40 ligand (CD40L) and RA synovial fluid, and significantly suppressed macrophage production of CD40L-induced IL-8, TNF, MMP-1 and MMP-10, LPS-induced MMP-1, MMP-7 and MMP-10 production, and spontaneous production of IL-6, PDGF, CXCL-9 and MMP-1 by RA synovial explants.

Conclusions Btk is expressed equivalently in RA and PsA synovial tissue, primarily in macrophages. Btk activity is needed to drive macrophage activation in response to multiple agonists relevant to inflammatory arthritis, and promotes RA synovial tissue cytokine and MMP production. Pharmacological targeting of Btk may be of therapeutic benefit in the treatment of RA and other inflammatory diseases.

  • Rheumatoid Arthritis
  • Inflammation
  • Cytokines
  • Chemokines

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