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

描述（由申请人提供）：风湿性关节炎（RA）是一种炎性疾病，其特征为破坏性多关节炎和炎症、基质降解和细胞增殖的严重改变。表现出侵袭性表型的滑膜细胞导致滑膜增生并侵入软骨和骨。这种破坏性炎症是由一些细胞内信号通路控制的，这些信号通路调节类风湿性滑膜内膜中的基因表达。先天免疫应答途径在滑膜活化和细胞募集到类风湿关节中起作用。先天传感器识别病毒、细菌和内源性产物，并诱导作为关键哨兵细胞因子的I型干扰素（IFNa和IFNb）的分泌。转录因子干扰素调节因子3（IRF 3）和IRF 7差异调节基因表达和I型IFN应答的反馈。我们提出组成型IRF 3和诱导型IRF 7以细胞特异性方式差异调节滑膜IFN诱导和炎症，从而改变关节炎的病程。我们推测，与IRF 3相比，IRF 7通过以细胞特异性方式改变IFN调节基因和其他促炎反应，在炎性关节炎的先天免疫中发挥反调节作用。使用滑膜细胞中的靶向敲除和组成性激活，将定义IRF 3和IRF 7在IFN调节的基因表达的激活中的相对贡献和细胞特异性作用。在滑膜细胞中特异性靶向IRF 3代表了抑制滑膜IFN刺激基因MMP以及细胞因子如IL-6和IL-8的新方法。本提案中计划的实验还将探索IRF 3和IRF 7对K/BxN抗体介导的炎症性关节炎小鼠模型的体内功能和相对贡献。由于IRF 7缺乏导致K/BxN模型中关节炎的增加，我们将探讨IRF 7激动剂可能代表炎性关节炎的新治疗方法的假设。我们的体内数据表明，诱导IRF 7的先天性受体激动剂代表了基于该模型的炎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，诱导IRF 7，代表了治疗炎性关节炎的新方法。我们还将评估胶原诱导的关节炎模型，以评估IRF 3和IRF 7在该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是在这两种关节炎模型中检测到的任何显著作用的核心。这一建议是有意义的，因为它将有助于了解RA的发病机制，无论是在人类滑膜细胞和关节炎模型的先天性和适应性免疫反应。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。 公共卫生相关性：虽然在过去十年中有了很大的改善，但类风湿性关节炎（RA）（炎性关节炎最常见和最具破坏性的形式之一）的治疗仍然是一个未满足的医疗需求。我们认为干扰素调节因子3（IRF 3）和IRF 7以细胞特异性方式调节滑膜干扰素诱导和炎症，从而改变关节炎的病程。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，并与NIAMS支持关节炎病因研究的使命相关。

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. PUBLIC HEALTH RELEVANCE: Although greatly improved over the past decade, treatment of rheumatoid arthritis (RA), one of the most common and destructive forms of inflammatory arthritis, remains an unmet medical need. We propose that interferon regulatory factor 3 (IRF3) and IRF7 regulate synovial interferon induction and inflammation in a cell specific manner that modifies the course of arthritis. These studies will have major implications for targeting the IRF transcription factor family to treat autoimmune and inflammatory diseases and are relevant to NIAMS mission to support research into the causes of arthritis.