IL-33 is induced in undifferentiated, non-dividing esophageal epithelial cells in eosinophilic esophagitis

J Travers,C E Miracle,J M Caldwell,M E Rothenberg,M Rochman,J A Besse

doi:10.1038/s41598-017-17541-5

J Travers, C E Miracle + Show 4 more

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https://doi.org/10.1038/s41598-017-17541-5

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Abstract

The molecular and cellular etiology of eosinophilic esophagitis (EoE), an emerging tissue-specific allergic disease, involves dysregulated gene expression in esophageal epithelial cells. Herein, we assessed the esophageal expression of IL-33, an epithelium-derived alarmin cytokine, in patients with EoE. IL-33 protein was markedly overexpressed within the nuclei of a subpopulation of basal layer esophageal epithelial cells in patients with active EoE compared to control individuals. IL-33 exhibited dynamic expression as levels normalized upon EoE remission. IL-33–positive basal epithelial cells expressed E-cadherin and the undifferentiated epithelial cell markers keratin 5 and 14 but not the differentiation marker keratin 4. Moreover, the IL-33–positive epithelial cells expressed the epithelial progenitor markers p75 and p63 and lacked the proliferation markers Ki67 and phospho-histone H3. Additionally, the IL-33–positive cells had low expression of PCNA. IL-33 expression was detected in ex vivo–cultured primary esophageal epithelial cells in a subpopulation of cells lacking expression of proliferation markers. Collectively, we report that IL-33 expression is induced in an undifferentiated, non-dividing esophageal epithelial cell population in patients with active EoE.

Highlights

Eosinophilic esophagitis (EoE) is an emerging chronic, food antigen-driven, inflammatory allergic disorder[1]
We report that patients with active EoE have markedly increased detection of interleukin 33 (IL-33) present in the nuclei of esophageal basal layer cells with high levels of E-cadherin, p75, p63, and keratins (KRT) 5 and 14 and low expression of proliferating cell nuclear antigen (PCNA)
Consistent with previous reports indicating increased rates of proliferation within the esophageal epithelium of patients with active EoE21,22, there were increased number of cells positive for Ki-6723, phospho-histone H324, and PCNA (Fig. 3C,D). In biopsies from both active EoE patients and control individuals, interpapillary basal layer (IBL) cells did not express Ki-67 (Fig. 3C,E) or phospho-histone H3 (Fig. 3D,E) and only had low expression of PCNA (Fig. 3C), which is strongly upregulated during S phase[25]. These results indicate that these IL-33–positive basal layer cells express markers consistent with being a non-dividing epithelial progenitor population

Summary

Introduction

Eosinophilic esophagitis (EoE) is an emerging chronic, food antigen-driven, inflammatory allergic disorder[1]. Intraperitoneal injection of recombinant IL-33 induces esophageal responses that mimic EoE, including eosinophil infiltration, increased proliferation of esophageal epithelial cells, and production of type 2-associated cytokines[13]. We report that patients with active EoE have markedly increased detection of IL-33 present in the nuclei of esophageal basal layer cells with high levels of E-cadherin, p75, p63, and keratins (KRT) 5 and 14 and low expression of proliferating cell nuclear antigen (PCNA). These IL-33–positive basal layer cells lack KRT4, Ki67, and phospho-histone H3. We propose that IL-33 is induced in an undifferentiated, mitotically inactive esophageal epithelial population in patients with EoE

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