title: Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice.
abstract: OBJECTIVE
  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-70(W163C)-mutant (SKG) mice injected intraperitoneally with β-1,3-glucan (curdlan).
  
  
  METHODS
  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.
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Queensland and Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Benham
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rehaume
authors.forename: Sumaira Z
authors.initials: SZ
authors.lastname: Hasnain
authors.forename: Jared
authors.initials: J
authors.lastname: Velasco
authors.forename: Athan C
authors.initials: AC
authors.lastname: Baillet
authors.forename: Merja
authors.initials: M
authors.lastname: Ruutu
authors.forename: Kristine
authors.initials: K
authors.lastname: Kikly
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.forename: Hsu-Wen
authors.initials: HW
authors.lastname: Tseng
authors.forename: Gethin P
authors.initials: GP
authors.lastname: Thomas
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Strutton
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000276:immunology; D005260:Female; D007079:Ileitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007108:Immune Tolerance / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism; D025241:Spondylarthritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D047071:beta-Glucans / Q000494:pharmacology*; D000097043:Interleukin-22
chemical_list: D000906:Antibodies; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D047071:beta-Glucans; D000097043:Interleukin-22; C098680:Il17a protein, mouse; C508841:Il23a protein, mouse; C528688:interleukin-23 receptor, mouse; C038459:curdlan; C033363:beta-1,3-glucan