Requirement of type I interferon signaling for arthritis triggered by double-stranded RNA
Article first published online: 29 DEC 2005
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 1, pages 148–157, January 2006
How to Cite
Magnusson, M., Zare, F. and Tarkowski, A. (2006), Requirement of type I interferon signaling for arthritis triggered by double-stranded RNA. Arthritis & Rheumatism, 54: 148–157. doi: 10.1002/art.21517
- Issue published online: 29 DEC 2005
- Article first published online: 29 DEC 2005
- Manuscript Accepted: 21 SEP 2005
- Manuscript Received: 3 JUN 2005
- 80-Year Foundation of King Gustaf V
- Capio Research Foundation
- Hiertas Foundation
- Thölens Foundation
- Goljes Foundation
- Swedish Association Against Rheumatism
- Swedish Research Council
- Lundberg Foundation
- Torsten and Ragnar Söderberg Foundation
- Swedish National Inflammation Network
- Nanna Svartz Foundation
- Göteborg Medical Society
- Börje Dahlin Foundation
- Göteborg University
Arthralgias and overt arthritides are often associated with viral infections. Viral infections expose the infected host to proinflammatory double-stranded RNA (dsRNA), which can cause joint inflammation and is a potent activator of interferon-α (IFNα). The aim of this study was to determine the role of IFNα and dsRNA-related signaling molecules in the onset of joint inflammation induced by viral dsRNA.
IFNα and different forms of RNA were injected into the knee joints of wild-type mice, mice lacking the type I interferon receptor (IFNAR−/−), and mice deficient in dsRNA-dependent protein kinase (PKR−/−). Histologic evidence of joint damage and the ability of splenocytes to produce cytokines in response to dsRNA or IFNα were assessed.
Viral dsRNA, but not short single-stranded RNA, induced arthritis. The arthritis was aggravated by intracellular delivery of dsRNA. The expression of PKR was not mandatory for dsRNA-induced joint inflammation. In contrast, IFNα/β signaling was important for dsRNA-induced joint inflammation because IFNAR−/− mice did not develop arthritis. Furthermore, intraarticular deposition of IFNα induced arthritis in PKR−/− and control mice, whereas IFNAR−/− mice were protected. The arthritogenic effect of IFNα was attenuated by in vivo depletion of monocyte/macrophages.
Arthritis triggered by dsRNA is not dependent on the expression of the dsRNA-signaling molecule PKR (or Toll-like receptor 3, as previously shown), but is associated with the ability to produce type I IFN and is critically dependent on type I IFN receptor signaling. The intrinsic arthritogenic properties of IFNα implicate a role of this cytokine in joint manifestations triggered by various interferogenic stimuli.