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Role of miR-146a in regulation of the acute inflammatory response to monosodium urate crystals
  1. Nicola Dalbeth1,
  2. Bregina Pool1,
  3. Odette M Shaw2,
  4. Jacquie L Harper2,
  5. Paul Tan1,
  6. Christopher Franklin1,
  7. Meaghan E House1,
  8. Jillian Cornish1,
  9. Dorit Naot1
  1. 1Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand
  2. 2Malaghan Institute for Medical Research, Wellington, New Zealand
  1. Correspondence to Dr Nicola Dalbeth, Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd, Grafton, Auckland 1023, New Zealand; n.dalbeth{at}auckland.ac.nz

Abstract

Objectives MicroRNAs (miRNA) are small non-coding RNAs that function as post-transcriptional repressors of gene expression. We hypothesised that miRNA regulate gene expression of proinflammatory cytokines in response to monosodium urate (MSU) crystals.

Methods We stimulated human monocytic THP-1 cells with MSU crystals and examined miRNA and proinflammatory cytokine gene expression. The effects of miR-146a overexpression were examined by transfecting THP-1 cells with miR-146a precursor. miR-146a expression was examined in the urate peritonitis model, in peripheral blood mononuclear cells from people with gout and control participants, and in gouty tophus samples.

Results MSU crystals increased miR-146a expression in THP-1 cells, but not other miRNA implicated in interleukin (IL)-1β regulation. Overexpression of miR-146a expression reduced MSU crystal-induced IL-1β, tumour necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and IL-8 gene expression. In the urate peritonitis model, reduced miR-146a expression was observed during the acute inflammatory response to MSU crystal injection. In people with intercritical gout, peripheral blood mononuclear cells expressed significantly higher levels of miR-146a, compared with normouricaemic and hyperuricaemic control participants and those with acute gout flares. Expression of miR-146a was also observed in all tophus samples.

Conclusions Collectively, these data suggest that miR-146a is a transcriptional brake that is lost during the acute inflammatory response to MSU crystals.

  • Gout
  • Inflammation
  • Cytokines

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