Targeting interleukin-23(p19) to improve intestinal barrier integrity in inflammatory bowel disease — ASN Events
  1. Schedule
  2. Poster Session Three
  3. Targeting interleukin-23(p19) to improve intestinal barrier integrity in inflammatory bowel disease

Targeting interleukin-23(p19) to improve intestinal barrier integrity in inflammatory bowel disease (#403)

Ran Wang 1 , Rohan Lourie 1 2 , Hui Tong 1 , Jakob Begun 1 2 , Timothy Florin 1 2 , Michael A. McGuckin 1 , Sumaira Z. Hasnain 1
  1. Inflammatory Disease Biology and Therapeutics, and Inflammatory Bowel Disease Group, Mater Research Institute - UQ, Brisbane, QLD, Australia
  2. Mater Adult Hospital, Mater Health Service, Brisbane, QLD, Australia

Background

Genome-wide association studies have identified IL-23R as an inflammatory bowel disease (IBD) associated gene. IL-23, a dimer composed of p40 and p19, promotes TH17  cells and ILC3’s,  directly recruits inflammatory macrophages and neutrophils to mucosal sites, and is linked to IBD pathogenesis. IL-23p19 expression in endothelial cells is associated with endothelial activation and increased leucocyte rolling. These functions identify IL-23 as a promising target for treating IBD. Winnie mice share similarities with human ulcerative colitis, developing spontaneous intestinal inflammation derived from an epithelial defect and driven by an IL-23/TH17-dominant inflammatory response. The aim of this study was to determine the effects and the mechanisms by which anti-IL-23 therapy suppresses colitis in Winnie mice.

Results

Two weeks treatment with anti-IL-23p19 antibody significantly ameliorated established colitis in Winnie mice. Interestingly, the treatment did not dampen the intestinal mRNA levels of inflammatory cytokines, including Il17a, Ifng and Il1b, suggesting that the mechanism of action may be other than by suppressing cytokine-production. Treatment was accompanied by diminished colonic neutrophil infiltration, reduced chemokine mRNA expression in colonic epithelial cells, and restored colonic goblet cell mucin production. Anti-IL-23p19 treatment was also associated with reduced intestinal endothelial cell activation in Winnie mice compared to isotype treated mice, which could contribute to reduced inflammatory cell recruitment. Here, we demonstrate for the first time that intestinal epithelial cells can produce IL-23p19, with mRNA expression increased in the stressed Winnie epithelial cells. Epithelial derived IL-23p19 may contribute to increased neutrophil recruitment in inflammation.

Conclusion

Neutralisation of IL-23p19 is likely to be efficacious in IBD by reducing epithelial cell chemokine production-mediated recruitment of inflammatory macrophages and neutrophils into the intestine. These effects, together with suppression of T-cell  and ILC3 activation, will help restore normal mucosal barrier integrity and intestinal homeostasis.

 

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