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

Asquith, D.L. et al. (2013) The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release. Annals of the Rheumatic Diseases, 72(12), pp. 2024-2031. (doi: 10.1136/annrheumdis-2012-202872) (PMID:23434566)

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Abstract

<p>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.</p> <p>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).</p> <p>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.</p> <p>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.</p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Reilly, Mr James and Asquith, Dr Darren and Kerr, Mrs Shauna and Gracie, Professor Alastair and Kurowska-Stolarska, Dr Mariola and Nijjar, Dr Jagtar
Authors: Asquith, D.L., Ballantine, L.E., Nijjar, J.S., Makdasy, M.K., Patel, S., Wright, P.B., Reilly, J.H., Kerr, S., Kurowska-Stolarska, M., Gracie, J.A., and McInnes, I.B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Annals of the Rheumatic Diseases
Publisher:B M J Group
ISSN:0003-4967
Published Online:23 February 2013
Copyright Holders:Copyright © 2013 BMJ Publishing Group
First Published:First published in Annals of the Rheumatic Diseases
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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