Promotion of inflammatory arthritis by interferon regulatory factor 5 in a mouse model

Pierre Duffau, Hanni Menn-Josephy, Carla M. Cuda, Salina Dominguez, Tamar R. Aprahamian, Amanda A. Watkins, Kei Yasuda, Paul Monach, Robert Lafyatis, Lisa M. Rice, G. Kenneth Haines, Ellen M. Gravallese, Rebecca Baum, Christophe Richez, Harris Perlman, Ramon G. Bonegio, Ian R. Rifkin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Objective Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development. Methods K/BxN serum-transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated. K/BxN arthritis was also induced in mice deficient in TRIF, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR7 to determine the pathways through which IRF5 might promote arthritis. In vitro studies were performed to determine the role of IRF5 in interleukin-1 (IL-1) receptor and TLR signaling. Results Arthritis severity was reduced in IRF5-deficient, TRIF-deficient, TLR3-deficient, and TLR7-deficient mice. The expression of multiple genes regulating neutrophil recruitment or function and bioactive IL-1β formation was reduced in the joints during active arthritis in IRF5-deficient mice. In vitro studies showed that TLR7 and the TRIF-dependent TLR3 pathway induce proinflammatory cytokine production in disease-relevant cell types in an IRF5-dependent manner. Conclusion Our findings indicate that IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating proinflammatory cytokine production downstream of TLR7 and TLR3. Since TLR7 and TLR3 are both RNA-sensing TLRs, this suggests that endogenous RNA ligands present in the inflamed joint promote arthritis development. These findings may be relevant to human RA, since RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are up-regulated in the joints of RA patients.

Original languageEnglish (US)
Pages (from-to)3146-3157
Number of pages12
JournalArthritis and Rheumatology
Volume67
Issue number12
DOIs
StatePublished - Dec 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Fingerprint

Dive into the research topics of 'Promotion of inflammatory arthritis by interferon regulatory factor 5 in a mouse model'. Together they form a unique fingerprint.

Cite this