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Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts
  1. Olga Sanchez-Pernaute1,2,
  2. Maria Filkova1,
  3. Antonio Gabucio2,
  4. Martin Klein1,
  5. Hanna Maciejewska-Rodrigues1,
  6. Caroline Ospelt1,
  7. Fabia Brentano1,
  8. Beat A Michel1,
  9. Renate E Gay1,
  10. Gabriel Herrero-Beaumont2,
  11. Steffen Gay1,
  12. Michel Neidhart1,
  13. Astrid Juengel1
  1. 1Center for Experimental Rheumatology, University Hospital Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland
  2. 2Rheumatology Division, Fundacion Jimenez Diaz, Autonoma University Madrid, Madrid, Spain
  1. Correspondence to Dr Olga Sanchez Pernaute, Rheumatology Division, Fundacion Jimenez Diaz University Hospital, Avda Reyes Catolicos 2; Madrid 28040, Spain; osanchez{at}fjd.es

Abstract

Objective Fibrin deposits are characteristic of the synovial tissues in rheumatoid arthritis (RA). Once citrullinated, fibrin becomes an autoantigen and is thought to contribute in this way to perpetuate the disease. Our study aimed to analyse the responses of RA synovial fibroblasts (RASF) to native and citrullinated fibrin.

Methods The transcriptome induced by fibrin in RASF was approached with whole-genome-based gene expression arrays. The upregulation of selected pro-inflammatory genes by fibrin was confirmed in additional primary cell cultures using quantitative PCR and ELISA. Citrullination reactions were carried out with recombinant human peptidylarginine deiminases (PAD) 2 and 4.

Results In the whole-genome array native fibrin was found to modulate the gene expression profile of RASF, particularly upregulating mRNA levels of several pro-inflammatory cytokines. The induction of interleukin (IL)-6 and IL-8 by fibrin was confirmed in additional samples at both the mRNA and the protein level. Blocking and knockdown experiments showed the participation of toll-like receptor (TLR)4 in the induction of both cytokines. As compared with the native macromolecule, PAD2-citrullinated fibrin induced significantly higher expression of the pro-inflammatory cytokines in these cells.

Conclusions Our results suggest that fibrin mediates inflammatory responses in RASF via a TLR4 pathway. In this way, fibrin and particularly its citrullinated form may contribute to sustain the cytokine burst in RA.

  • Rheumatoid Arthritis
  • Fibroblasts
  • Chemokines
  • Ant-CCP

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