Background/Purpose: Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacteria in gut and lung. Recently, there is emerging evidence that IL-22 plays a dual role in the pathogenesis of several autoimmune diseases like psoriasis and multiple sclerosis. In this study we aimed to unravel the pathogenic effects of IL-22 on joint inflammation and destruction, and its therapeutic potential during experimental arthritis.

Methods: First, endogenous IL-22 was blocked using neutralizing antibodies during collagen-induced arthritis (CIA), and the effects were studied on X-ray and by histology. To further investigate the pathogenic effects of IL-22, an adenoviral construct overexpressing murine IL-22 (AdIL-22) or a control virus was intra-articularly injected into naïve knee joints of C57Bl/6 mice, and at various time points the knee joints were clinically and histologically assessed for inflammation and destruction. Synovial biopsies and washouts were obtained for analysis of cytokines, chemokines and MMPs on mRNA expression (RT-QPCR) and protein levels (Luminex). In addition, in vitro stimulated fibroblasts were used to confirm these IL-22 effects. Finally, IL-22 was overexpressed during experimental arthritis induced by the injection of bacterial (SCW) fragments into the knee joint, to study IL-22’s contribution as Th17 cytokine in the aggravation of an acute joint inflammation.

Results: Anti-IL-22 treatment after the onset of CIA significantly reduced arthritis progression, and had even more dramatic therapeutic effects on radiographic destruction. Adenoviral overexpression of IL-22 in naïve and arthritic joints was used to further investigate the pathogenic effects of IL-22. Overexpression of IL-22 in a naïve knee joint resulted in an acute joint inflammation which was relatively mild and short-lasting in comparison to other proinflammatory cytokines like TNF and IL-1. The increased influx of cells by AdIL-22 was accompanied by elevated levels of the chemokines MCP-1 and KC, as well as IL-6 and S100A9. Overexpression of IL-22 induced significant proteoglycan depletion from the articular cartilage, but did not cause severe and irreversible destruction to cartilage and bone, in contrast to the significant upregulation of MMP3, MMP9 and RANKL in the synovial tissue and by the in vitro stimulated fibroblasts. We therefore expected that in synergy with other inflammatory stimuli during SCW-induced arthritis, IL-22 overexpression would become far more potent and destructive. Surprisingly, however, IL-22 overexpression during experimental arthritis significantly suppressed joint inflammation, suggesting a more complex mechanism of action of this dual cytokine.

Conclusion: Since both overexpression of IL-22 as well as blocking endogenous IL-22 with neutralizing antibodies provide protection against further disease progression in experimental arthritis, the exact mechanism of action of IL-22 needs to be identified before IL-22-based treatments can be applied in clinical treatment of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treating-experimental-arthritis-with-adenoviral-overexpression-of-il-22-or-with-blocking-antibodies-against-endogenous-il-22-both-reduces-inflammation-and-destruction/