Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model

Abstract

Objective Polymorphisms in the transcription factor IRF5 are associated with an increased risk of developing RA. This study was done to determine the role of IRF5 in 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, TLR2, TLR3, TLR4 and TLR7 to determine pathways through which IRF5 might promote arthritis. In-vitro studies were performed to determine the role of IRF5 in 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 pro-inflammatory cytokine production in disease relevant cell types in an IRF5-dependent manner. Conclusion IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating pro-inflammatory cytokine production downstream of TLR7 and TLR3. As 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 as RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are upregulated in the joints of RA patients.

TLRs, future potential therapeutic targets for RA

“…Consistent with this observation, K/BxN serum transfer arthritis was markedly reduced in TLR3−/− mice through a mechanism that was partially due to interferon regulatory factor (IRF)5 signaling [121]. …”

“…Others documented that CIA was alleviated in TLR7−/− mice, due to the suppression of the IL-17 response and elevation of joint Tregs [125]. Similarly, in the K/BxN serum transfer arthritis model, joint inflammation was attenuated in TLR7−/− compared to wild type mice in part due to reduced serum levels of IL-1β, CXCL1, CXCL10 and CCL3 [121]. …”

MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2

“…IRF5 can be activated in a MyD88-dependent manner by TLR7 or TLR9 agonists [39][40][41]. In the context of some inflammatory stimuli, TLR3-mediated TRIF signaling can synergize with MyD88 for full IRF5 activation [42,43]. However, pathogenic CHIKV-induced iNOS expression in dLN monocytes was independent of TRIF (S5A and S5B Fig).…”

Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound‐Guided Synovial Biopsies in Rheumatoid Arthritis

“…Synovial macrophages are highly activated, express elevated levels of Toll-like receptor 2 (TLR-2), TLR-4, and TLR-7 (14,15), and contribute directly and indirectly to synovial inflammation and the destruction of cartilage and bone through the production of degradative enzymes, cytokines, and chemokines. Further, TLR-2, TLR-3, and TLR-7 play essential roles in the development of inflammatory arthritis in mice (16)(17)(18). More importantly, macrophages are the central producers of interleukin-1b (IL-1b), IL-6, and TNF, which comprise the 3 essential proinflammatory cytokines that contribute to RA pathogenesis.…”