Role of Interferon Regulatory Factor 7 in Serum-Transfer Arthritis Regulation of Interferon-β Production

Objective. Innate immune responses activate synoviocytes and recruit inflammatory cells into the rheumatoid joint. Type I interferons (IFNs) play a role in autoimmunity, and IFN gene transcription is activated by IFN-regulatory factors (IRFs) in response to innate sensor recognition. The purpose of this study was to examine the effect of genetic deficiency of IRF-7 in a passive K/BxN serum-transfer model of arthritis. Methods. Passive-transfer arthritis was induced in IRF-7(-/-) mice, and additional groups were treated with IFN beta or poly(I-C). Clinical arthritis scoring, histologic assessment, micro-computed tomography, and synovial tissue quantitative polymerase chain reaction analysis were performed. Mouse serum was analyzed by enzyme-linked immunosorbent assay (ELISA). Results. In the passive K/BxN serum-transfer model, arthritis severity was significantly increased in IRF-7(-/-) mice compared with wild-type (WT) mice. In addition, expression of IFN beta in synovium and serum was decreased, potentially contributing to increased arthritis. IRF-7(-/-) mice injected with replacement IFN beta had a decrease in arthritis. Poly(I-C) treatment diminished arthritis in IRF-7(-/-) mice, restored synovial IFN beta gene expression, and increased serum levels of IFN beta. In vitro studies demonstrated that poly(I-C) stimulation of fibroblast-like synoviocytes (FLS) from IRF-7(-/-) mice resulted in increased induction of proinflammatory gene expression as compared with FLS from WT mice; however, IFN beta expression was not significantly different. In contrast, peritoneal macrophages from IRF-7(-/-) mice showed significantly less induction of IFN beta in response to poly(I-C) stimulation. Conclusion. IRF-7 deficiency exacerbates arthritis and replacement treatment with IFN beta or poly(I-C) decreases arthritis severity. Both macrophage- and synoviocyte-specific roles of IRF-7 likely contribute to the increased arthritis. IRF-7 might play an antiinflammatory role in passive-transfer arthritis through regulation of macrophage IFN beta production.