Background/Purpose: High interleukin-22 (IL-22) levels are detected in serum and synovial fluid of rheumatoid arthritis (RA) patients and have been shown to positively correlate with disease activity markers and more erosive disease. The role of IL-22 in autoimmunity and inflammation appears to be greatly contradictory, being both pro- and anti-inflammatory. Previous work in other disease models suggested that the presence of IL-17 determines the inflammatory effect of IL-22, being protective in the absence and pathogenic in the presence of IL-17. The purpose of our study was to further unravel the role of IL-22 during experimental arthritis, in particular focusing on the cytokine interactions within the inflammatory environment.

Methods: To investigate the potential of IL-22 to drive joint inflammation and destruction, IL-22 was overexpressed in murine knee joints using an adenoviral construct (AdIL-22), and synovial biopsies and whole joints were collected for mRNA/protein expression analysis and histological scoring of joint pathology. To study the interaction of IL-22 within the disease cytokine network, AdIL-22 was injected intra-articularly as single cytokine, or combined with a second vector overexpressing TNFα, IL-17 or IL-1β. Furthermore, we studied the effect of local IL-22 overexpression on two experimental arthritis models: SCW and K/BxN serum transfer arthritis. Our second strategy involved using IL-22-deficient mice, which were crossed with IL-1Ra-deficient mice that spontaneously develop T cell-driven arthritis. Besides the effect of IL-22-deficiency on arthritis incidence and severity, we also investigated how the lack of IL-22 signaling affected the responsiveness to anti-IL-17 therapy in this IL-17-driven model.

Results: Despite the significantly enhanced synovial mRNA expression of pro-inflammatory and pro-destructive genes like IL-6, KC, S100A8 and RANKL, surprisingly IL-22-overexpression did not result in any sign of joint pathology in the knee joints of naïve mice. Furthermore, IL-22 neither aggravated disease severity during both models of innate immune-driven experimental arthritis, nor did it affect IL-17-, IL-1β-, or TNFα-induced joint inflammation when overexpressed in combination with other cytokines. Interestingly, in comparison to the spontaneous arthritis development in classical IL-1Ra^-/- mice, the absence of IL-22 significantly reduced disease incidence and severity in this model. While the arthritis incidence in regular IL-1Ra^-/- mice reached up to 95% at the age of 15 weeks, IL-22^-/- x IL-1Ra^-/- mice only showed 50% disease onset. In line with suppressed disease severity, anti-hnRNP autoantibodies were lowered in IL-22^-/- x IL-1Ra^-/- mice. No effects were observed on T cell responses. Remarkably, in the absence of IL-22 the therapeutic efficacy of anti-IL-17 treatment on arthritis progression in these mice was lost.

Conclusion: This study not only confirms the pro-inflammatory role of IL-22 in the development and progression of experimental arthritis, it also demonstrates a novel role in the formation of anti-hnRNP antibodies. Finally, we demonstrated that IL-17 is not a determinant for the pro- or anti-inflammatory character of IL-22 in experimental arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-17-is-not-a-determinant-for-the-pro-or-anti-inflammatory-character-of-interleukin-22-in-experimental-arthritis/