Regulation of the type I interferon response by IRFs in inflammatory arthritis

描述（由申请人提供）：类风湿关节炎（RA）是一种炎症性疾病，以破坏性多关节炎和炎症、基质降解和细胞增殖的关键改变为特征。滑膜细胞表现出侵袭性表型，导致滑膜增生并侵入软骨和骨。这种破坏性炎症是由一些调节类风湿性滑膜内膜基因表达的细胞内信号通路控制的。先天免疫反应途径在类风湿关节滑膜活化和细胞募集中发挥作用。先天传感器识别病毒、细菌和内源性产物，并诱导I型干扰素（IFNa和IFNb）的分泌，作为关键的前哨细胞因子。转录因子干扰素调节因子3 （IRF3）和IRF7差异调节I型IFN应答的基因表达和反馈。我们提出，组成型IRF3和诱导型IRF7以细胞特异性的方式调节滑膜IFN诱导和炎症，从而改变关节炎的进程。我们假设，与IRF3相比，IRF7通过改变ifn调节的基因和其他细胞特异性的促炎反应，在炎性关节炎的先天免疫中起反调节作用。利用滑膜细胞的靶向敲除和组成性激活，将确定IRF3和IRF7在激活ifn调节基因表达中的相对贡献和细胞特异性作用。在滑膜细胞中特异性体外靶向IRF3代表了一种抑制滑膜ifn刺激基因、MMP以及细胞因子如IL-6和IL-8的新方法。本课题拟开展的实验还将探讨IRF3和IRF7在K/BxN抗体介导的小鼠炎症性关节炎模型中的体内功能及其相对贡献。因为在K/BxN模型中，IRF7缺乏导致关节炎增加，我们将探索IRF7激动剂可能代表炎症性关节炎的新治疗方法的假设。我们的体内数据表明，诱导IRF7的先天受体激动剂代表了基于该模型的炎症性关节炎的潜在治疗方法。在我们看来，拟议的研究是创新的，因为数据表明TLR激动剂而不是传统的TLR拮抗剂方法可以诱导IRF7，并代表了治疗炎性关节炎的新方法。我们还将评估拼贴诱导的关节炎模型，以评估IRF3和IRF7在这种炎症性关节炎模型中对适应性反应的相对贡献。将产生骨髓嵌合体，以确定基质细胞或造血细胞是否对这两种关节炎模型中检测到的任何显著影响起核心作用。这一建议具有重要意义，因为它将有助于理解人类滑膜细胞和先天和适应性免疫反应的关节炎模型中RA的发病机制。这些研究将对靶向IRF转录因子家族治疗自身免疫性和炎症性疾病具有重要意义。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an inflammatory disease characterized by destructive polyarthritis and critical alterations in inflammation, matrix degradation, and cellular proliferation. Synoviocytes exhibiting an aggressive phenotype result in synovial hyperplasia and invasion into cartilage and bone. This destructive inflammation is controlled by a number of intracellular signaling pathways that regulate gene expression in the rheumatoid synovial intimal lining. The innate immune response pathways play a role in synovial activation and cell recruitment into the rheumatoid joint. Innate sensors recognize viral, bacterial, and endogenous products and induce secretion of type I interferon (IFNa and IFNb) that serve as key sentinel cytokines. The transcription factors interferon regulatory factor 3 (IRF3) and IRF7 differentially regulate gene expression and feedback of type I IFN response. We propose that constitutive IRF3 and inducible IRF7 differentially regulate synovial IFN induction and inflammation in a cell specific manner that modifies the course of arthritis. We hypothesize that IRF7, compared with IRF3, plays a counter-regulatory role in innate immunity in inflammatory arthritis by altering IFN-regulated genes and other pro-inflammatory responses in a cell specific manner. Using targeted knockdown and constitutive activation in synoviocytes, the relative contributions and cell specific roles of IRF3 and IRF7 in activation of IFN-regulated gene expression will be defined. Specific in vitro targeting of IRF3 in synoviocytes represents a novel approach to inhibiting synovial IFN-stimulated genes, MMP, as well as cytokines such as IL-6 and IL-8. The experiments planned in this proposal will also explore the in vivo function and relative contributions of IRF3 and IRF7 to the K/BxN antibody-mediated mouse model of inflammatory arthritis. Because IRF7 deficiency resulted in increased arthritis in the K/BxN model, we will explore the hypothesis that IRF7 agonists might represent a novel treatment approach to inflammatory arthritis. Our in vivo data suggests that innate receptor agonists that induce IRF7 represent potential treatment approaches for inflammatory arthritis based on this model. The proposed research, in our opinion, is innovative because the data suggest TLR agonists, rather than the traditional TLR antagonist approach, induce IRF7 and represent a novel approach to the treatment of inflammatory arthritis. We will also evaluate the collage-induced arthritis model to assess the relative contributions of IRF3 and IRF7 to adaptive responses in this inflammatory arthritis model. Bone marrow chimeras will be generated to determine whether stromal or hematopoietic cells are central to any significant effects detected in both of these arthritis models. This proposal is significant because it will contribute to the understanding of the pathogenesis of RA both in human synoviocytes and arthritis models of both innate and adaptive immune responses. These studies will have major implications for targeting the IRF transcription factor family to treat autoimmune and inflammatory diseases.