Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice
Benham, H., Rehaume, L. M., Hasnain, S. Z., Velasco, J., Baillet, A. C., Ruutu, M., Kikly, K., Wang, R., Tseng, H. W., Thomas, G. P., Brown, Matthew A., Strutton, G., McGuckin, M. A., & Thomas, R. (2014) Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis and Rheumatology, 66(7), pp. 1755-1767.
Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin-23 (IL-23) receptor signaling in the development of SpA and IBD, and IL-23 overexpression 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 subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP-70W163C-mutant (SKG) mice injected intraperitoneally with β-1,3-glucan (curdlan).
Eight weeks after curdlan injection in wild-type or IL-17A-/- SKG or BALB/c mice, pathology was scored in tissue sections. Mice were treated with anti-IL-23 or anti-IL-22. Cytokine production and endoplasmic reticulum (ER) stress were determined in affected organs.
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 ER stress, goblet cell dysfunction, and proinflammatory cytokine production. IL-17A was pathogenic, while IL-22 was protective against ileitis. IL-22+CD3- innate-like cells were increased in lamina propria mononuclear cells of ileitis-resistant BALB/c mice, which developed ileitis after curdlan injection and anti-IL-22.
In response to systemic β-1,3-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/IL-22-dependent enthesitis. Innate IL-22 production promotes ileal tolerance.
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|Item Type:||Journal Article|
|Additional Information:||No file attached.|
|Keywords:||beta 1, 3 glucan, interleukin 17, interleukin 22, interleukin 23, protein kinase ZAP 70, animal experiment, animal model, arthritis, article, cytokine production, endoplasmic reticulum stress, enthesitis, goblet cell, ileitis, ileum, lamina propria, mononuclear cell, mouse, nonhuman, pathogenesis, priority journal, spondylarthritis, Animals, Antibodies, beta-Glucans, Disease Models, Animal, Female, Immune Tolerance, Interleukin-17, Interleukin-23 Subunit p19, Interleukins, Intestines, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Receptors, Interleukin|
|Divisions:||Current > Schools > School of Biomedical Sciences
Current > Institutes > Institute of Health and Biomedical Innovation
|Deposited On:||25 Sep 2015 02:53|
|Last Modified:||25 Sep 2015 02:53|
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