Session Title: Cytokines, Mediators, and Gene Regulation
Session Type: Abstract Submissions (ACR)
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.
D. S. Gilchrist,
A. R. Fraser,
G. J. Graham,
I. B. McInnes,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/microrna-155-regulates-chemokines-and-chemokine-receptors-in-rheumatoid-arthritis-monocyte/