RT Journal Article
SR Electronic
T1 Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1400
OP 1406
DO 10.1136/annrheumdis-2012-201906
VO 72
IS 8
A1 Olga Sanchez-Pernaute
A1 Maria Filkova
A1 Antonio Gabucio
A1 Martin Klein
A1 Hanna Maciejewska-Rodrigues
A1 Caroline Ospelt
A1 Fabia Brentano
A1 Beat A Michel
A1 Renate E Gay
A1 Gabriel Herrero-Beaumont
A1 Steffen Gay
A1 Michel Neidhart
A1 Astrid Juengel
YR 2013
UL http://ard.bmj.com/content/72/8/1400.abstract
AB 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.