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* = Presenting author

P077. Emerging role of the interleukin (IL)-33/ST2 axis in gut mucosal wound healing and epithelial repair

L.R. Lopetuso1,2, H.N. Senkfor1, C. De Salvo1, X.M. Wang1, A. Gasbarrini2, F. Scaldaferri2, T.T. Pizarro1, 1Case Western Reserve University – School of Medicine, Pathology, Cleveland, United States, 2Catholic University of Rome, Internal Medicine/Gastroenterology Division, Rome, Italy

Background

Increasing evidence confirms that IL-33 and its receptor, ST2, are critical factors in IBD, specifically UC, with recent studies suggesting their role in wound healing and epithelial restoration/repair. The aim of our study was to assess the modulation and role of the IL-33/ST2 axis following acute epithelial injury and mucosal repair in dextran sodium sulphate (DSS)-induced colitic mice.

Methods

3% DSS was administered for 5d to C57/BL6 mice to induce colitis. DSS was then replaced with regular drinking water for 1 wk to evaluate the epithelial repair and mucosal healing processes. Mice were sacrificed either after DSS challenge or after recovery; control mice (CT) not exposed to DSS were similarly sacrificed, at which time colons were harvested. Body weight, occult blood test, and stool consistency were measured daily to calculate the Disease Activity Index (DAI), and histological evaluation of colons was performed using an established scoring system. IHC and qPCR were done on full-thickness colons for IL-33 and ST2 localization and mRNA expression, respectively.

Results

Administration of 3% DSS resulted in increased body weight loss and DAI, but not significant mortality vs. CT mice. More severe colitis was observed following DSS+recovery vs. after 5d of DSS (5.500±0.456 vs. 3.125±0.554; p < 0.02), with an increased presence of regenerating epithelium overlying frank mucosal ulcerations during the recovery phase; no colitis was found in CT mice. IL-33 mRNA transcripts were dramatically elevated after DSS (3.089±0.612-fold, p < 0.03), and even more so following DSS+recovery (5.166±0.981-fold, p < 0.02) vs. CT. Interestingly, ST2 mRNA expression was also increased after DSS+recovery vs. CT (3.759±0.357-fold, p < 0.002), while no difference was found between 5d of DSS challenge and CT. These results were confirmed using IHC wherein intense IL-33 and ST2 staining was present within the inflamed and ulcerated mucosa of DSS-treated mice. In particular, ST2 staining was more evident during the recovery phase following DSS, notably localized to subepithelial myofibroblasts in close proximity to areas of re-epithelialization.

Conclusion

Our results suggest an important role for IL-33/ST2 in gut mucosal wound healing after acute epithelial injury. Further studies are underway to determine the precise mechanism(s) involved in the repair process and to explore the IL-33/ST2 axis as a potential therapeutic target for IBD-associated mucosal wound healing.