Impact of IL-1 signalling on experimental uveitis and arthritis
- Stephen R Planck1,2,3,
- April Woods1,
- Jenna S Clowers1,4,
- Martin J Nicklin5,
- James T Rosenbaum1,2,3,
- Holly L Rosenzweig1,4,6
- 1Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA
- 2Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon, USA
- 3Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
- 4 Department of Rheumatology, VA Medical Center, Portland, Oregon, USA
- 5Division of Genomic Medicine, University of Sheffield, Sheffield, UK
- 6Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, USA
- Correspondence to Holly L Rosenzweig, Casey Eye Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA;
- Received 3 August 2011
- Accepted 29 November 2011
- Published Online First 20 January 2012
Background Uveitis, or inflammatory eye disease, is a common extra-articular manifestation of many systemic autoinflammatory diseases involving the joints. Anakinra (recombinant interleukin (IL)-1 receptor antagonist (Ra)) is an effective therapy in several arthritic diseases; yet, few studies have investigated the extent to which IL-1 signalling or IL-1Ra influences the onset and/or severity of uveitis.
Objective To seek possible links between arthritis and uveitis pathogenesis related to IL-1 signalling.
Methods The eyes of IL-1Ra-deficient BALB/c mice were monitored histologically and by intravital videomicroscopy to determine if uveitis developed along with the expected spontaneous arthritis in ankles and knees. Expression levels of IL-1R and its negative regulators (IL-1Ra, IL-1RII, IL-1RAcP and single Ig IL-1R-related molecule) in eye and joint tissues were compared. Differences in uveitis induced by intraocular injection of lipopolysaccharide (LPS) in mice lacking IL-1R or IL-1Ra were assessed.
Results Deficiency in IL-1Ra predisposes to spontaneous arthritis, which is exacerbated by previous systemic LPS exposure. The eye, however, does not develop inflammatory disease despite the progressive arthritis or LPS exposure. Organ-specific expression patterns for IL-1Ra and negative regulators of IL-1 activity were observed that appear to predict predisposition to inflammation in each location in IL-1Ra knockout mice. The eye is extremely sensitive to locally administered LPS, and IL-1Ra deficiency markedly exacerbates the resulting uveitis.
Conclusion This study demonstrates that IL-1Ra plays an important role in suppressing local responses in eyes injected with LPS and that there is discordance between murine eyes and joints in the extent to which IL-1Ra protects against spontaneous inflammation.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.