Inflammatory Mediators promote the development and progression of metaplasia in the stomach

Abstract

Spasmolytic polypeptide-expression metaplasia (SPEM) develops in the atrophic stomach and progresses to an intestinalized SPEM in the setting of inflammation. Different immune deficient mouse models determined that T-cells, B-cells, IFN gamma and neutrophils are not essential for the progression to an intestinalized SPEM. However, studies using macrophage-depleted mice found that specifically M2 macrophages were necessary for SPEM to become intestinalized. Efforts to understand macrophage-derived factors that promote the advancement of metaplasia led to RNA-sequencing of gastric macrophages in the setting of SPEM and intestinalized SPEM. A novel profile of activated gastric macrophages revealed that IL-33 is significantly upregulated in the setting of intestinalized SPEM. Inducing parietal cell loss in IL33 knock out mice uncovered an essential role for IL-33 in the transdifferentiation of mature chief cells into SPEM cells. Furthermore, IL-33 is required for the polarization of recruited macrophages towards M2a. Thus establishing a vital role for IL-33 in the development of metaplasia and macrophage polarization in response to acute parietal cell loss in the stomach.