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Suppression of the Effector Phase of Inflammatory Arthritis by Double-Stranded RNA Is Mediated by Type I IFNs¹

Anna Yarilina^*, Edward DiCarlo and Lionel B. Ivashkiv^2,*,

^* Arthritis and Tissue Degeneration Program and Department of Laboratory Medicine, Hospital for Special Surgery, New York, NY 10021; and Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021

Innate immune receptors that recognize nucleic acids, such as TLRs and RNA helicases, are potent activators of innate immunity that have been implicated in the induction and exacerbation of autoimmunity and inflammatory arthritis. Polyriboinosine-polyribocytidylic acid sodium salt (poly(IC)) is a mimic of dsRNA and viral infection that activates TLR3 and the RNA helicases retinoic acid-induced gene-1 and melanoma differentiation-associated gene-5, and strongly induces type I IFN production. We analyzed the effects of systemic delivery of poly(IC) on the inflammatory effector phase of arthritis using the collagen Ab-induced and KRN TCR-transgenic mouse serum-induced models of immune complex-mediated experimental arthritis. Surprisingly, poly(IC) suppressed arthritis, and suppression was dependent on type I IFNs that inhibited synovial cell proliferation and inflammatory cytokine production. Administration of exogenous type I IFNs was sufficient to suppress arthritis. These results suggest a regulatory role for innate immune receptors for dsRNA in modulating inflammatory arthritis and provide additional support for an anti-inflammatory function of type I IFNs in arthritis that directly contrasts with a pathogenic role in promoting autoimmunity in systemic lupus.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (to L.B.I.) and was conducted in a facility constructed with support from Research Facilities Improvement Program Grant C06-RR12538-01 from the National Center for Research Resources, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Lionel B. Ivashkiv, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: ivashkivl{at}hss.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; poly(IC), polyriboinosine-polyribocytidylic acid sodium salt; RIG-I, retinoic acid-induced gene-1; Mda5, melanoma differentiation-associated gene-5; CAIA, collagen Ab-induced arthritis; K/BxN, KRN TCR-transgenic mouse; VEGF, vascular endothelial growth factor.

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