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.
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.
Authors: Vineet I Patel; J Leland Booth; Elizabeth S Duggan; Steven Cate; Vicky L White; David Hutchings; Susan Kovats; Dennis M Burian; Mikhail Dozmorov; Jordan P Metcalf Journal: J Immunol Date: 2016-12-28 Impact factor: 5.422
Authors: S Pérez-Baos; J I Barrasa; P Gratal; A Larrañaga-Vera; I Prieto-Potin; G Herrero-Beaumont; R Largo Journal: Br J Pharmacol Date: 2017-08-03 Impact factor: 8.739
Authors: Kirsty E Waddington; George A Robinson; Beatriz Rubio-Cuesta; Eden Chrifi-Alaoui; Sara Andreone; Kok-Siong Poon; Iveta Ivanova; Lucia Martin-Gutierrez; Dylan M Owen; Elizabeth C Jury; Inés Pineda-Torra Journal: Proc Natl Acad Sci U S A Date: 2021-05-25 Impact factor: 11.205
Authors: Mariola Kurowska-Stolarska; Stefano Alivernini; Emma Garcia Melchor; Aziza Elmesmari; Barbara Tolusso; Clare Tange; Luca Petricca; Derek S Gilchrist; Gabriele Di Sante; Chantal Keijzer; Lynn Stewart; Clara Di Mario; Vicky Morrison; James M Brewer; Duncan Porter; Simon Milling; Ronald D Baxter; David McCarey; Elisa Gremese; Greg Lemke; Gianfranco Ferraccioli; Charles McSharry; Iain B McInnes Journal: Nat Commun Date: 2017-06-22 Impact factor: 14.919
Authors: Franziska D Weber; Isabelle Weinhofer; Angelika Einwich; Sonja Forss-Petter; Zahid Muneer; Harald Maier; Willi H A Weber; Johannes Berger Journal: PLoS One Date: 2014-07-31 Impact factor: 3.240