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The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release
  1. Darren Lee Asquith1,
  2. Lucy E Ballantine2,
  3. Jagtar Singh Nijjar1,
  4. Manhal Khuder Makdasy1,
  5. Sabina Patel3,
  6. Pamela B Wright1,
  7. James H Reilly1,
  8. Shauna Kerr1,
  9. Mariola Kurowska-Stolarska1,
  10. J Alastair Gracie1,
  11. Iain B McInnes1
  1. 1Department of Immunology, Infection and Inflammation, College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
  2. 2Institute of Child Health, Alder Hey Children's Hospital, University of Liverpool, Liverpool, UK
  3. 3Core Discovery Technology Group, GlaxoSmithKline, Stevenage, UK
  1. Correspondence to Professor Iain B McInnes, College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK; Iain.McInnes{at}glasgow.ac.uk

Abstract

Objectives Macrophages are central to the inflammatory processes driving rheumatoid arthritis (RA) synovitis. The molecular pathways that are induced in synovial macrophages and thereby promote RA disease pathology remain poorly understood.

Methods We used microarray to characterise the transcriptome of synovial fluid (SF) macrophages compared with matched peripheral blood monocytes from patients with RA (n=8).

Results Using in silico pathway mapping, we found that pathways downstream of the cholesterol activated liver X receptors (LXRs) and those associated with Toll-like receptor (TLR) signalling were upregulated in SF macrophages. Macrophage differentiation and tumour necrosis factor α promoted the expression of LXRα. Furthermore, in functional studies we demonstrated that activation of LXRs significantly augmented TLR-driven cytokine and chemokine secretion.

Conclusions The LXR pathway is the most upregulated pathway in RA synovial macrophages and activation of LXRs by ligands present within SF augments TLR-driven cytokine secretion. Since the natural agonists of LXRs arise from cholesterol metabolism, this provides a novel mechanism that can promote RA synovitis.

  • Cytokines
  • Rheumatoid Arthritis
  • Inflammation
  • Synovial Fluid

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