- D3.540 - Sources of IL-13 in Acute Versus Chronic Models of Eosinophilic Esophagitis

We previously developed inducible (iEoE33) and constitutive (EoE33) mouse models of eosinophilic esophagitis (EoE) that recapitulate key disease features and are dependent on IL-13 signaling. Both models are driven by epithelial overexpression of IL-33, a type 2 inflammatory cytokine that is elevated in the esophageal epithelium of patients with EoE. In this study, we sought to identify the cellular sources of IL-13 in these models.

To examine the cellular sources of IL-13, we crossed our mouse models of EoE (iEoE33 and EoE33) with mice deficient in eosinophils (∆dblGATA) or lymphocytes (IL-7R^-/-). iEoE33 mice were administered doxycycline-infused chow (625 mg/kg) ad libitum for 2 weeks for EoE induction.  Disease reversal was examined for 4 weeks following induction. Pathology was assessed by histology and immunohistochemistry for IL-33, eosinophil peroxidase, CD4, and Ki-67. Single cell sequencing and ELISA for IL-13 and food-specific immunoglobulins were performed on esophageal homogenates.

Single-cell RNA sequencing identified ILC2s as a major population of IL-13–producing cells in the acute EoE model (iEoE33). Consistent with this finding, iEoE33 mice deficient in IL-7R exhibited no esophageal pathology and markedly reduced IL-13 levels compared with iEoE33 controls (iEoE33 109.20 pg/mg vs. iEoE33xIL-7R^-/- 10.92 pg/mg, p<0.001).  In contrast, mast cells, T cells, and eosinophils were identified as sources of IL-13 in the chronic EoE model (EoE33). IL-13 levels in the chronic model were partially dependent on eosinophils, as EoE33x∆dblGATA exhibited reduced IL-13 levels compared with EoE33 controls (64.89 pg/mg vs. 39.91 pg/mg, p<0.01). Notably, induced disease pathology in iEoE33 mice resolved over four weeks and was accompanied by a progressive decline in IL-13 levels, consistent with a transient, ILC2-driven inflammatory response.

The cellular sources of IL-13 differ between acute and chronic EoE models, with ILC2s serving as the predominant source during disease induction and a shift toward mast cells, T cells, and eosinophils in the chronic setting.