Requirement of type I interferon signaling for arthritis triggered by double-stranded RNA

Objective. 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-alpha (IFN alpha). The aim of this study was to determine the role of IFN alpha and dsRNA-related signaling molecules in the onset of joint inflammation induced by viral dsRNA. Methods. IFN alpha 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 IFNa were assessed. Results. 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, IFN alpha/beta signaling was important for dsRNA-induced joint inflammation because IFNAR(-/-) mice did not develop arthritis. Furthermore, intraarticular deposition of IFNa induced arthritis in PKR-/- and control mice, whereas IFNAR(-/-) mice were protected. The arthritogenic effect of IFN alpha was attenuated by in vivo depletion of monocyte/macrophages. Conclusion. 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 IFN alpha implicate a role of this cytokine in joint manifestations triggered by various interferogenic stimuli.