OP027 IL-33/ST2 axis sustains gut mucosal wound healing and cancerogenesis in colitis-associated colorectal cancer

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Background: IL-33/ST2 axis is important in IBD.Emerging evidence suggests its role in epithelial proliferation and contribution to inflammation-driven tumorigenesis. Our aim was to characterize the its contribution in the DSS and AOM/DSS model of colitis.

Methods: C57/BL6 wild-type (WT), IL-33 KO and ST2 KO mice were given one dose of AOM followed by two cycles of 3% DSS for 7d. WT mice, injected with vehicle and given drinking water were used as controls (CT). At 8 wks post AOM injection mice were sacrificed. IHC, immunofluorescence (IF) and qPCR were done. FACS analysis was performed on resected, isolated polyps. 3% DSS was administered for 5d to WT, IL-33 KO and ST2 KO mice. DSS was replaced with drinking water for 2 wks (recovery period). Another group of WT mice received DSS for 5d and IL-33 or vehicle (VEH) every other day during the recovery period. Mice were sacrificed either after DSS challenge or after 1 or 2 wks of recovery.

Results: In AOM/DSS model IL-33, ST2L, and sST2 mRNA transcripts were dramatically elevated in WT vs. CT mice. IHC of treated WT mice revealed localization of ST2 to the intestinal epithelium in tissues immediately adjacent to tumors, while within the tumors themselves, ST2+ cells displayed a spindle/fibroblast-like morphology with a unique distribution throughout the polyps. Little to no staining for ST2 was present in CT.Using IF, ST2 co-localized with αSMA in polyps; ST2 was not exclusive for αSMA+ cells. At FACS analysis ST2 was mainly expressed by CD3/CD8+ cytotoxic T cells, and CD11b+CD11c- and CD11b+CD11c+ myeloid cells. Non-hematopoietic cells (CD45-) also expressed ST2.At 5 weeks post AOM injection WT had already pre-tumorous lesions, while IL-33 KO and ST2 KO mice showed their absence with a more impressive mucosal inflammation, likely due to reduced epithelial proliferation and repair caused by the absence of IL-33 signaling. At sacrifice, increased number and size of polyps were observed in WT vs. IL-33KO and ST2KO mice. More severe colitis was observed following DSS+1wk recovery vs. after 5d of DSS, which decreased after DSS+2wks recovery. ST2 staining was more evident during the recovery phase following DSS, localized to subepithelial myofibroblasts in proximity to areas of re-epithelialization. Both IL-33 and ST2 KO mice showed increased colonic inflammation after 2 wks recovery compared to after 5d DSS and vs WT.IL-33 treatment resulted in increased body weight, reduced DAI, and decreased colonic inflammation after 2 wks recovery vs. VEH.

Conclusions: Our results suggest that activation of the IL-33/ST2 axis sustains mucosal healing and tumorigenesis in the murine model of colitis-associated CRC.

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