The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release

被引:35
作者
Asquith, Darren Lee [1 ]
Ballantine, Lucy E. [2 ]
Nijjar, Jagtar Singh [1 ]
Makdasy, Manhal Khuder [1 ]
Patel, Sabina [3 ]
Wright, Pamela B. [1 ]
Reilly, James H. [1 ]
Kerr, Shauna [1 ]
Kurowska-Stolarska, Mariola [1 ]
Gracie, J. Alastair [1 ]
McInnes, Iain B. [1 ]
机构
[1] Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Dept Immunol Infect & Inflammat, Glasgow G12 8TA, Lanark, Scotland
[2] Univ Liverpool, Alder Hey Childrens Hosp, Inst Child Hlth, Liverpool L69 3BX, Merseyside, England
[3] GlaxoSmithKline, Core Discovery Technol Grp, Stevenage, Herts, England
基金
英国医学研究理事会;
关键词
Cytokines; Rheumatoid Arthritis; Inflammation; Synovial Fluid; TOLL-LIKE RECEPTORS; TISSUE MACROPHAGES; ACTIVATION; EXPRESSION; DIFFERENTIATION; MEMBRANE; INFILTRATION; INFLAMMATION; CHOLESTEROL; BIOMARKER;
D O I
10.1136/annrheumdis-2012-202872
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:2024 / 2031
页数:8
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