Journal
ANNALS OF THE RHEUMATIC DISEASES
Volume 72, Issue 12, Pages 2024-2031Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2012-202872
Keywords
Cytokines; Rheumatoid Arthritis; Inflammation; Synovial Fluid
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Funding
- MASTER SWITCH European community grant
- Medical Research Council (UK)
- Nuffield Foundation Oliver Bird Rheumatism programme
- Arthritis Research UK
- Iraqi Ministry of Higher Education and Scientific Research
- Versus Arthritis [19213] Funding Source: researchfish
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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 promoted the expression of LXR. 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.
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