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

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Abstract
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-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. Methods 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. 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, 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. 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 IFNα implicate a role of this cytokine in joint manifestations triggered by various interferogenic stimuli.

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