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.
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.
|Sweeney, Susan E; Corr, Maripat; Kimbler, Trevor B (2012) Role of interferon regulatory factor 7 in serum-transfer arthritis: regulation of interferon-? production. Arthritis Rheum 64:1046-56|
|Sweeney, Susan E (2011) Targeting interferon regulatory factors to inhibit activation of the type I IFN response: implications for treatment of autoimmune disorders. Cell Immunol 271:342-9|
|Sweeney, Susan E; Kimbler, Trevor B; Firestein, Gary S (2010) Synoviocyte innate immune responses: II. Pivotal role of IFN regulatory factor 3. J Immunol 184:7162-8|