Microrna-155 regulates chemokines and chemokine receptors in Rheumatoid Arthritis monocyte

Elmesmari, A., Gilchrist, D. S., Fraser, A. D., Vaughan, D., McQueenie, R., Graham, G. , Brewer, J. , McInnes, I. B. and Kurowska-Stolarska, M. (2012) Microrna-155 regulates chemokines and chemokine receptors in Rheumatoid Arthritis monocyte. In: American College of Rheumatology & Association of Rheumatology Health Professionals, Annual Scientific Meeting, Washington DC, USA, 9-14 Nov 2012, S384. (doi:10.1002/art.37735)

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Abstract

Background/Purpose: Rheumatoid arthritis (RA) is characterized by synovial tissue inflammation leading to joint destruction. Monocytes/macrophages are major effector cells in RA synovitis, principally by releasing TNF- α, IL-6 and other inflammatory cytokines and chemokines. MicroRNAs are a recently discovered class of post-transcriptional regulators –in particular miR-155 is upregulated in RA synovial macrophages where it regulates cytokine expression. We hypothesized that miR-155 regulates migration of monocytes by modulating the chemokine and chemokine receptor system.

Methods: Peripheral blood (PB) was obtained from healthy controls and RA patients who met the 2010 ACR/EULAR diagnostic criteria. Purified CD14+ PB monocytes obtained by magnetic bead isolation were transfected with miR-155 mimic or scrambled mimic using an N-TER nanoparticle system. Taqman Low Density Array and Luminex multiplex assay was used to evaluate chemokine receptor gene expression and chemokine production, respectively. Absolute copy numbers of miR-155 transcripts in PB and SF monocytes of RA and healthy controls were assessed by QPCR. The role of mir155 was investigated further using bone marrow monocytes (BMM) from miR-155 / and WT mice.

Results: RA PB and SF macrophages showed higher copy number of miR-155 compared with healthy controls. Overexpression of miR-155 induced the production of chemokines CCL4, CCL5, CCL8 and CCL22 in RA monocytes and CCL3 in both RA and healthy controls. However, overexpression of miR-155 in healthy control and RA monocytes did not affect the production of CCL2, CCL7, CCL21, CXCL5, CXCL8, CXCL7, CXCL10 and CX3CL1. Analysis of chemokine receptors in BMM of miR-155 / and WT mice revealed significantly higher levels of CCR1, CCR2, CCR5 and CXCR4 in miR-155 deficient cells suggesting that miR-155 can act as a negative regulator of these receptors in homeostatic state. TLR-4 ligand significantly suppressed expression of these receptors in both WT and miR-155 / cells. Analysis of 3’UTRs of chemokine and chemokine receptor (TargetScan) suggests that miR-155 likely interferes with signaling pathways implicated in chemokine and chemokine receptor system expression.

Conclusion: Deregulation of miR-155 in RA monocytes can contribute to the production of pro-inflammatory chemokines by these cells and to their accumulation at sites of inflammation.

Item Type:Conference Proceedings
Additional Information:Supplement: Arthritis and Rheumatism, 64(10): S384
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Fraser, Dr Alasdair and Brewer, Professor James and Gilchrist, Dr Derek and Kurowska-Stolarska, Dr Mariola and Vaughan, Ms Diane and McQueenie, Dr Ross and Graham, Professor Gerard
Authors: Elmesmari, A., Gilchrist, D. S., Fraser, A. D., Vaughan, D., McQueenie, R., Graham, G., Brewer, J., McInnes, I. B., and Kurowska-Stolarska, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Arthritis and Rheumatism
Publisher:Wiley Blackwell
ISSN:0004-3591
ISSN (Online):1529-0131

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