title: The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release.
abstract: OBJECTIVE
  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.
authors: Department of Immunology, Infection and Inflammation, College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, , Glasgow, UK.
authors: Darren Lee
authors: DL
authors: Asquith
authors: Lucy E
authors: LE
authors: Ballantine
authors: Jagtar Singh
authors: JS
authors: Nijjar
authors: Manhal Khuder
authors: MK
authors: Makdasy
authors: Sabina
authors: S
authors: Patel
authors: Pamela B
authors: PB
authors: Wright
authors: James H
authors: JH
authors: Reilly
authors: Shauna
authors: S
authors: Kerr
authors: Mariola
authors: M
authors: Kurowska-Stolarska
authors: J Alastair
authors: JA
authors: Gracie
authors: Iain B
authors: IB
authors: McInnes
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013582:Synovial Fluid / Q000378:metabolism*; D013585:Synovitis / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha
keywords: Cytokines; Inflammation; Rheumatoid Arthritis; Synovial Fluid