Eosinophil Specialization Is Regulated by Exposure to the Esophageal Epithelial Microenvironment

Abstract

Distinct subsets of eosinophils are reported in inflammatory and healthy tissues, yet the functions of uniquely specialized eosinophils and the signals that elicit them, particularly in eosinophilic esophagitis (EoE), are not well understood. Herein, we report an ex-vivo system wherein freshly isolated human eosinophils were cocultured with esophageal epithelial cells and disease-relevant pro-inflammatory (IL-13) or pro-fibrotic (TGF-β) cytokines. Compared with untreated cocultures, IL-13 increased expression of CD69 on eosinophils, whereas TGF-β increased expression of CD81, CD62L, and CD25. Eosinophils from IL-13-treated cocultures demonstrated increased secretion of GRO-α, IL-8, and M-CSF and also generated increased extracellular peroxidase activity following activation. Eosinophils from TGF-β-treated cocultures secreted increased IL-6 and exhibited increased chemotactic response to CCL11 compared with eosinophils from untreated or IL-13-treated coculture conditions. When eosinophils from TGF-β-treated cocultures were cultured with fibroblasts, they upregulated SERPINE1 expression and fibronectin secretion by fibroblasts compared with eosinophils that were cultured with GM-CSF, alone. Translational studies revealed that CD62L was heterogeneously expressed by eosinophils in patient biopsies. Our results demonstrate that disease-relevant pro-inflammatory and pro-fibrotic signals present in the esophagus of EoE patients cause distinct profiles of eosinophil activation and gene expression.

Keywords: Eosinophilic esophagitis; allergy; eosinophil; epithelium; granulocyte; innate imunity.