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

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.

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 J 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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