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

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    Authors
    Duffau, Pierre
    Menn-Josephy, Hanni
    Cuda, Carla M.
    Dominguez, Salina
    Aprahamian, Tamar R.
    Watkins, Amanda A.
    Yasuda, Kei
    Monach, Paul
    Lafyatis, Robert
    Rice, Lisa M.
    Kenneth Haines, G. 3rd.
    Gravallese, Ellen M.
    Baum, Rebecca
    Richez, Christophe
    Perlman, Harris
    Bonegio, Ramon G.
    Rifkin, Ian R.
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    UMass Chan Affiliations
    Department of Medicine, Division of Rheumatology
    Document Type
    Journal Article
    Publication Date
    2015-12-01
    Keywords
    Musculoskeletal Diseases
    Rheumatology
    
    Metadata
    Show full item record
    Link to Full Text
    http://dx.doi.org/10.1002/art.39321
    Abstract
    OBJECTIVE: 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. 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, 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. 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-1beta 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. CONCLUSION: 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.
    Source
    Arthritis Rheumatol. 2015 Dec;67(12):3146-57. doi: 10.1002/art.39321. Link to article on publisher's site
    DOI
    10.1002/art.39321
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/30554
    PubMed ID
    26315890
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1002/art.39321
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