IL-33 triggers early eosinophil-dependent events leading to metaplasia in a chronic model of gastritis-prone mice

IL-33/IL-1F11 is an important mediator for the development of Th2-driven inflammatory disorders and has also been implicated in the pathogenesis of GI-related cancers, including gastric carcinoma. We therefore sought to mechanistically determine IL-33's potential role as a critical factor linking chronic inflammation and gastric carcinogenesis using gastritis-prone SAMP1/YitFc (SAMP) mice METHODS: SAMP and (parental control) AKR mice were assessed for baseline gastritis and progression to metaplasia. Expression/localization of IL-33 and its receptor, ST2/IL-1R4, were characterized in corpus tissues, and both activation and neutralization studies were performed targeting the IL-33/ST2 axis. Dissection of immune pathways leading to metaplasia were evaluated, including eosinophil depletion studies using anti-IL-5/anti-CCR3 treatment RESULTS: Progressive gastritis and ultimately, intestinalized spasmolytic polypeptide-expressing metaplasia (SPEM) was detected in SAMP stomachs, which was absent in AKR, but could be moderately-induced with exogenous, recombinant (r)IL-33. Robust peripheral (bone-marrow, BM) expansion of eosinophils and local recruitment of both eosinophils and IL-33-expressing M2 macrophages into corpus tissues were evident in SAMP. Interestingly, IL-33 blockade did not affect BM-derived expansion and local infiltration of eosinophils, but markedly decreased M2 macrophages and SPEM features, while eosinophil depletion caused a significant reduction in both local IL-33-producing M2 macrophages and SPEM in SAMP CONCLUSIONS: IL-33 promotes metaplasia and the sequelae of eosinophil-dependent downstream infiltration of IL-33-producing M2 macrophages leading to intestinalized SPEM in SAMP, suggesting that IL-33 represents a critical link between chronic gastritis and intestinalizing metaplasia that may serve as a potential therapeutic target for pre-neoplastic conditions of the GI tract.