Emerging Insights into the Inflammatory Phenotypes of Eosinophilic Esophagitis

Eosinophilic Esophagitis (EoE) is an immune-mediated disease associated with pronounced Type 2 allergic inflammation. Here we review the literature addressing the cellular and molecular mechanisms that drive inflammation in EoE, and the consequences of inflammation for epithelial damage and fibrotic remodeling. Emerging data identifies the dynamic interplay of a complex network of cytokines and immune cells that orchestrate EoE related inflammation. Significant insight into inflammatory cascades achieved through preclinical studies using cultured human cells and mouse models collectively underscores the interplay of IL-5, IL-13, and eotaxin in mucosal remodeling, immune cell recruitment, and activation. Although questions remain surrounding the specific initiating factors in EoE onset, evidence exists for involvement of environmental allergens or chemical irritants that damage the epithelium and trigger release of inflammatory alarmins including IL-33, which in turn activate resident mast cells and lymphocytes to secrete Type 2 cytokines. In addition to immune cells, the basal epithelium and lamina propria fibroblasts are particularly important to the inflammatory cascade, as they secrete additional cytokines when stimulated with IL-13. Improved understanding of the complex intercellular dynamics within the inflamed esophagus through next-generation single-cell sequencing and molecular studies are poised to identify the critical features of the inflamed esophagus, address tissue changes in response to steroid or biologic treatment, and determine when and how chronic inflammation may progress to fibrostenotic remodeling to identify novel therapeutic targets.