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A1.22 IL-22 Drives the initiation and augmentation of TH17-dependent experimental arthritis
  1. Debbie M Roeleveld,
  2. Renoud J Marijnissen,
  3. Wim B van den Berg,
  4. Marije I Koenders
  1. 1Radboud University Medical Center, Experimental Rheumatology, Nijmegen, The Netherlands

Abstract

Background Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that leads to progressive destruction of cartilage and bone. IL-22 and IL-22-producing T helper cells are elevated in RA patients, suggesting a role for this cytokine in the pathogenesis of this disease. Interestingly, IL-22 is a dual cytokine with both proinflammatory and anti-inflammatory properties, and therefore its exact role in RA pathology requires further investigation.

Objectives The aim of this study was to explore the role of IL-22 in the initiation and augmentation of a spontaneous model of experimental arthritis by using gene knockout mice and neutralizing antibodies for IL-22. In addition, we aimed to determine the influence of IL-22 on T cell subsets and cytokines in our mouse model.

Methods IL-1Ra-deficient mice develop spontaneous arthritis due to excess IL-1 signalling, and we previously demonstrated the importance of IL-17 and Th17 cells in this model (Koenders, Arthritis Rheum 2008). To investigate the role of IL-22 in this Th17-dependent arthritis model, we compared IL-1Ra-/- x IL-22WT mice to mice lacking both IL-1Ra and IL-22. Joint swelling was scored weekly, and mice were sacrificed at the age of fifteen weeks. In addition, IL-1Ra-deficient mice were treated for 4 weeks with anti-IL-22 neutralizing antibodies after the onset of arthritis to inhibit disease progression.

Results IL-1Ra-/- mice also deficient for IL-22 showed reduced incidence of arthritis, as well as reduced joint swelling and bone erosion. In addition, Th1, Th17, and regulatory T cell numbers were decreased in spleen and lymph nodes of mice lacking IL-22. Furthermore, IL-1Ra-deficient mice treated with anti-IL-22 antibodies after the clinical onset of arthritis showed reduced progression on inflammation and significant inhibition on bone erosion. This indicates that not only the onset but also the progression of arthritis is dependent on IL-22. Interestingly, reduced IL-17 serum levels were found after IL-22 blocking, suggesting a not previously observed feedback loop of IL-22 on Th17 cells.

Conclusion These findings suggest that the Th17 cytokine IL-22 plays an important role both in initiation and augmentation of experimental arthritis, and might therefore be an interesting new target in RA treatment.

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