Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33-basophil axis in mice

Abstract

Background: Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder characterized by accumulation of eosinophils in the esophagus. EoE often coexists with atopic dermatitis, a chronic inflammatory skin disease. The impaired skin barrier in patients with atopic dermatitis has been suggested as an entry point for allergic sensitization that triggers development of EoE.

Objective: We sought to define the mechanisms whereby epicutaneous sensitization through a disrupted skin barrier induces development of EoE.

Methods: To elicit experimental EoE, mice were epicutaneously sensitized with ovalbumin (OVA), followed by intranasal OVA challenge. Levels of esophageal mRNA for T_H2 cytokines and the IL-33 receptor Il1rl1 (St2) were measured by using quantitative PCR. Esophageal eosinophil accumulation was assessed by using flow cytometry and hematoxylin and eosin staining. In vivo basophil depletion was achieved with diphtheria toxin treatment of Mcpt8^DTR mice, and animals were repopulated with bone marrow basophils. mRNA analysis of esophageal biopsy specimens from patients with EoE was used to validate our findings in human subjects.

Results: Epicutaneous sensitization and intranasal challenge of wild-type mice resulted in accumulation of eosinophils and upregulation of T_H2 cytokines and St2 in the esophagus. Disruption of the IL-33-ST2 axis or depletion of basophils reduced these features. Expression of ST2 on basophils was required to accumulate in the esophagus and transfer experimental EoE. Expression of IL1RL1/ST2 mRNA was increased in esophageal biopsy specimens from patients with EoE. Topical OVA application on unstripped skin induced experimental EoE in filaggrin-deficient flaky tail (ft/ft) mice but not in wild-type control or ft/ft.St2^-/- mice.

Conclusion: Epicutaneous allergic sensitization promotes EoE, and this is critically mediated through the IL-33-ST2-basophil axis.

Keywords: Basophils; IL-33; ST2; eosinophilic esophagitis; filaggrin; skin barrier.