Eosinophil-Epithelial Cell Crosstalk at Mucosal Barriers: From Homeostatic Regulation to Disease Pathogenesis

Eosinophils are multifunctional granulocytes that reside constitutively within mucosal tissues, where they engage in bidirectional communication with the epithelial cells lining the respiratory and gastrointestinal (GI) tracts. Once regarded solely as terminal effectors of the type 2 immunity, eosinophils are now recognized as key regulators of epithelial homeostasis and barrier integrity. Epithelial cells initiate crosstalk by releasing the alarm cytokines such as interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and IL-25, which drive eosinophil recruitment, activation, and tissue retention. Conversely, eosinophils modulate epithelial function through the release of granule proteins, cytokines, and growth factors with both damaging and reparative consequences. In the airway, this crosstalk underpins the pathogenesis of eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), in part via eosinophil-derived mediators that disrupt tight junction integrity and fuel remodeling. In the GI tract, homeostatic eosinophils support villous architecture, epithelial turnover, and goblet cell differentiation through microbiota-driven IL-33 signals and neuropeptide-mediated neuroimmune pathways, whereas dysregulated crosstalk promotes eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD). This review synthesizes recent research to delineate the molecular mechanisms of eosinophil-epithelial crosstalk across mucosal compartments, highlight tissue-specific differences and shared mechanistic themes, and discuss the implications of these findings for targeted therapy.