Background/Purpose: The loss of intestinal barrier integrity is a key contributor to gut inflammation, however the mechanism behind this dysregulation is not well understood. The ZAP-70^W163C BALB/c (SKG) mouse model of Spondyloarthritis (SpA) develops IL-23-dependent Crohn’s-like ileitis after systemic curdlan administration, with fecal dysbiosis, ileal goblet cell depletion and ER stress. IL-24 is associated with ER stress and apoptosis and increased levels were observed in inflammatory bowel disease (IBD) and SpA. To help elucidate the mechanism behind intestinal barrier dysfunction and goblet cell depletion in IBD, we assessed the role of IL-24 in ileal ER stress-mediated apoptosis in SKG mice.

Methods: SKG and control BALB/c ileum was analysed by histology and immunofluorescence (IF). Ileal epithelial cells were analysed by flow cytometry. ER stress was induced with thapsigargin in the MUC2^hi human colonic epithelial cell line LS174T in the presence of IL-24 or control siRNA. Gene expression was analysed by RT-qPCR and protein by flow cytometry.

Results: Naïve SKG ileum has fecal dysbiosis. In SKG ileum, expression of Il24 and ER stress marker transcripts were increased relative to BALB/c ileum. By IF, IL-24 localised to the ileal goblet cells. UEA-1 expression in Ep-CAM+ intestinal epithelial cells was significantly increased, indicating increased mucin production in SKG mice compared to BALB/c. IL-24 knockdown in LS174T epithelial cells in vitro increased ER stress and apoptosis including increased CHOP, DR5 and active caspase-3 expression.

Conclusion: IL-24, a goblet cell-specific cytokine in small intestine mitigates ER stress-induced apoptosis in mucin-producing epithelial cells. This suggests that ER stress-associated IL-24 in SKG ileum is insufficient to prevent the cascade to IBD that commences with goblet cell apoptosis and epithelial barrier breakdown.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/goblet-cell-specific-anti-apoptotic-role-of-interleukin-24-in-spondyloarthritis-associated-ileitis/