Boston University School of Medicine, Boston, Massachusetts, and Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux and Université de Bordeaux, CNRS UMR 5164, Bordeaux, France.
Boston University School of Medicine, Boston, Massachusetts.
Arthritis Rheumatol. 2015 Dec;67(12):3146-57. doi: 10.1002/art.39321.
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.
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.
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.
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.
转录因子干扰素调节因子 5（IRF5）的多态性与类风湿关节炎（RA）的发病风险增加有关。本研究旨在确定 IRF5 在关节炎发展的小鼠模型中的作用。
在缺乏 IRF5 的小鼠或仅在髓样细胞中缺乏 IRF5 的小鼠中诱导 K/BxN 血清转移关节炎，并评估关节炎的严重程度。还在缺乏 TRIF、Toll 样受体 2（TLR2）、TLR3、TLR4 和 TLR7 的小鼠中诱导 K/BxN 关节炎，以确定 IRF5 可能促进关节炎的途径。进行体外研究以确定 IRF5 在白细胞介素 1（IL-1）受体和 TLR 信号传导中的作用。
IRF5 缺陷型、TRIF 缺陷型、TLR3 缺陷型和 TLR7 缺陷型小鼠的关节炎严重程度降低。在 IRF5 缺陷型小鼠的活动性关节炎期间，关节中调节中性粒细胞募集或功能和生物活性 IL-1β 形成的多个基因的表达减少。体外研究表明，TLR7 和依赖 TRIF 的 TLR3 途径以 IRF5 依赖的方式诱导疾病相关细胞类型中促炎细胞因子的产生。
我们的发现表明，IRF5 有助于炎症性关节炎的发病机制。这至少部分是由于 IRF5 在介导 TLR7 和 TLR3 下游的促炎细胞因子产生中的作用。由于 TLR7 和 TLR3 都是 RNA 感应 TLR，这表明在炎症关节中存在的内源性 RNA 配体促进关节炎的发展。这些发现可能与人类 RA 相关，因为在滑液中存在能够激活 TLR7 和 TLR3 的 RNA，并且在 RA 患者的关节中 TLR7 和 TLR3 上调。
