Objective: Spondyloarthropathies (SpA) occur in 1% of the population, and include ankylosing spondylitis and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis and IBD. Genetic studies implicate IL-23 receptor signaling in the development of SpA and IBD, and IL-23 over-expression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However in genetically-prone individuals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or sub-clinical gut inflammation of ankylosing spondylitis. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We determined the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP70W163C-mutant (SKG) mice injected i.p. with beta-1,3-glucan (curdlan).
Methods: Eight weeks after curdlan injection of wild type or IL-17-deficient SKG or BALB/c mice, pathology was scored in tissue sections. Mice were treated with anti-IL-23 or anti-IL22. Cytokine production and endoplasmic reticulum stress were determined in affected organs. Results: In curdlan-treated SKG mice arthritis, enthesitis and ileitis were IL-23-dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it amplified endoplasmic reticulum stress, goblet cell dysfunction and pro-inflammatory cytokine production. IL-17A was pathogenic while IL-22 was protective of ileitis. IL-22+CD3- innate-like cells were increased in lamina propria of ileitis-resistant BALB/c mice, which developed ileitis after curdlan and anti-IL-22.
Conclusion: In response to systemic beta-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/22-dependent enthesitis. Innate IL-22 production promotes ileal tolerance.