Background/Purpose: , IL-23 is required for the expansion and maintenance of T cells and innate cells secreting IL-17 and IL-22. These cytokines are important for control of fungal infections. Genetic studies implicate IL-23 receptor signalling in the pathogenesis of spondyloarthropathies. Spondyloarthritis and Crohn’s-like ileitis develop in an IL-23-dependent fashion in ZAP70-mutant SKG mice, which have deficient T cell receptor signalling. Our aim was to determine the role of IL-23, IL-17 and IL-22 in pathogenesis of spondyloarthritis and ileitis in this model.

Methods: , SKG mice or IL-17A deficient SKG mice were injected intraperitoneally with curdlan (1,3-D β-glucan) to induce disease. Anti-mouse IL-22, anti-IL-23 or isotype control antibodies were given i.p one day before curdlan, and weekly until sacrifice and anti-mouse IL-23 and IL-17A or isotype control antibodies were given in weekly doses commencing three weeks after i.p curdlan in a treatment regime. Outcomes were measured by clinical and histological scoring. Cytokines were measured by quantitative RT-PCR and in supernatants of cultured tissue explants.

Results: Curdlan induced spondyloarthritis in 100% and ileitis in 60% of SKG mice. Weekly anti-IL-23 treatment of SKG mice from induction suppressed development of spondyloarthritis and decreased the severity of ileitis. In curdlan-treated IL-17A deficient SKG mice, or SKG mice treated with anti-IL-17 from induction, spondyloarthritis and ileitis were less severe than control treated mice. In absence of IL-17A, peripheral enthesitis was particularly spared. Treatment with anti-IL-23 or anti-IL-17 three weeks after induction improved spondyloarthritis and ileitis, and anti-IL-23 was significantly more beneficial than anti-IL17. In contrast, anti-IL-22 modestly suppressed arthritis, increased anti-proteoglycan auto antibodies, and exacerbated ileitis. IL-23 mRNA and protein were expressed within days of induction, and increased over time in the ileum, but not in serum, lymph nodes or joint.

Conclusion: In curdlan-treated SKG mice, initiation and perpetuation of spondyloarthritis is dependent on IL-23, likely derived from the gut. IL-17A is particularly associated with enthesitis. Ileal inflammation is dependent on IL-23 and IL-17A and protected by IL-22. The data suggest that beta-glucan promotes IL-23 secretion, with protective and pathogenic consequences in different tissues through T cell cytokines downstream.  Defective T cell signalling in SKG mice not only hinders negative selection of self-reactive T cells but also microbial defence, potentially enhancing the requirement for innate immune mechanisms, including IL-23,  IL-17 and IL-22 for host protection.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/protective-and-pathogenic-effects-of-the-il-23-family-of-cytokines-in-spondyloarthropathy-in-skg-mice/