IL-23 Mediates Psoriasis-like Inflammation in the SKG Mouse Model of Spondyloarthropathy

Helen Benham¹, Linda Rehaume¹, Athan Baillet¹, Zaied Bhuyan¹, Jaclyn Bowman¹, Dimeng Pang¹, Kristine Kikly², Geoffrey Strutton³, Matthew Brown¹ and Ranjeny Thomas¹, ¹University of Queensland Diamantina Institute, Brisbane, Australia, ²Biotechnology Discovery Research, Eli Lilly and Co, Indianapolis, IN, ³Department of Pathology, Princess Alexandra Hospital, Brisbane, Australia

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: IL-23, psoriasis, spondylarthritis and spondylarthropathy

Session Information

Title: Spondyloarthropathies and Psoriatic Arthritis - Pathogenesis, Etiology

Session Type: Abstract Submissions (ACR)

Background/Purpose

Psoriasis (Ps) is a common immune-mediated inflammatory skin disease and is a well- recognised extra-articular manifestation of the spondyloathopathies (SpA). Genetic studies implicate IL-23 signalling in the pathogenesis of both Ps and SpA. Spondyloarthritis and psoriasis-like disease develop in an IL-23-dependent fashion in ZAP70-mutant SKG mice, which have deficient T cell receptor signaling. We characterized curdlan (1,3-D β-glucan) induced psoriasis-like inflammation in SKG mice, investigating the role of IL-23, IL-22/IL-17, regulatory T cells (Tregs) and microbiota.

Methods

SKG mice, IL-17A-deficient SKG mice, Germ Free SKG mice and Foxp3-DTR 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. Recombinant IL-23 or PBS was administered intra-dermally into ear skin. Outcomes were measured by clinical and histological scoring; cytokines and by qRT-PCR and in supernatants of cultured tissue explants by ELISA and CBA.

Results

Curdlan induced psoriasis-like inflammation in addition to spondyloarthritis in 100% of SKG mice. SKG skin lesions showed a histological phenotype similar to human Ps with elevated constitutive levels of IL-23a(p19) and increased secretion of both IL-17 and IL-22, 7 days after curdlan. Neutralisation of both IL-23 and IL-22 suppressed development of skin inflammation, in contrast IL-17A-deficient SKG mice were only partially spared. Germ Free (GF) SKG mice failed to develop significant skin inflammation after curdlan, however colonization of GF-SKG mice with a limited microbiota induced mild psoriasis-like inflammation. Tregs modulated the severity of skin inflammation through the suppression of IL-23 secretion. Intradermal injection of IL-23 induced IL-22 mediated, microbiota dependent psoriasis-like inflammation in naïve SKG mice.

Conclusion

In curdlan-treated SKG mice IL-23-driven psoriasis-like inflammation is induced in the setting of spondyloarthritis. The skin inflammation recapitulates several features of human Ps and is dependent on the relative contributions of IL-17, IL-22, microbiota and the balance of Tregs and T effector cells.

Disclosure:

H. Benham,
None;

L. Rehaume,
None;

A. Baillet,
None;

Z. Bhuyan,
None;

J. Bowman,
None;

D. Pang,
None;

K. Kikly,
None;

G. Strutton,
None;

M. Brown,
None;

R. Thomas,
None.

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