Altered esophageal histamine receptor expression in Eosinophilic Esophagitis (EoE): implications on disease pathogenesis.

Jamie Merves,Eduardo D Ruchelli,Diana M Lim,Kara Dods,Mei-Lun Wang,Hiroshi Nakagawa,Prasanna Modayur Chandramouleeswaran,Isha Mehta,Jonathan M Spergel,Amanda B Muir,Alain J Benitez,Anna J Lee,Claudia Daniela Andl

doi:10.1371/journal.pone.0114831

Jamie Merves, Eduardo D Ruchelli + Show 11 more

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https://doi.org/10.1371/journal.pone.0114831

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Abstract

Eosinophilic Esophagitis (EoE) is a chronic allergic disorder, whose pathobiology is incompletely understood. Histamine-producing cells including mast cells and basophils have been implicated in EoE. However, very little is currently known about the role of histamine and histamine receptor (HR) expression and signaling in the esophageal epithelium. Herein, we characterized HR (H1R, H2R, H3R, and H4R) expression in human esophageal biopsies and investigate the role of histamine signaling in inducible cytokine expression in human esophageal epithelial cells in vitro. HR expression was quantified in esophageal biopsies from non-EoE control (N = 23), inactive EoE (<15 eos/hpf, N = 26) and active EoE (>15 eos/hpf, N = 22) subjects using qRT-PCR and immunofluorescent localization. HR expression and histamine-mediated cytokine secretion were evaluated in human primary and telomerase-immortalized esophageal epithelial cells. H1R, H2R, and H4R expression were increased in active EoE biopsies compared to inactive EoE and controls. H2R was the most abundantly expressed receptor, and H3R expression was negligible in all 3 cohorts. Infiltrating eosinophils expressed H1R, H2R, and H4R, which contributed to the observed increase in HR in active subjects. H1R and H2R, but not H3R or H4R, were constitutively expressed by primary and immortalized cells, and epithelial histamine stimulation induced GM-CSF, TNFα, and IL-8, but not TSLP or eotaxin-3 secretion. Epithelial priming with the TLR3 ligand poly (I:C) induced H1R and H2R expression, and enhanced histamine-induced GM-CSF, TNFα, and IL-8 secretion. These effects were primarily suppressed by H1R antagonists, but unaffected by H2R antagonism. Histamine directly activates esophageal epithelial cytokine secretion in vitro in an H1R dependent fashion. However, H1R, H2R and H4R are induced in active inflammation in EoE in vivo. While systemic antihistamine (anti-H1R) therapy may not induce clinical remission in EoE, our study suggests that further study of histamine receptor signaling in EoE is warranted and that targeting of additional histamine receptors may lead to novel treatment strategies for this important disease.

Highlights

Eosinophilic esophagitis (EoE) is a chronic food antigen-mediated disease characterized by eosinophil infiltration into the esophageal epithelium [1]
Histamine receptors are expressed in the human esophagus in vivo histamine receptor (HR) expression has been studied in epithelial cells in other models such as the bronchial epithelium [15] and epidermal keratinocytes [16,26], HR expression in the esophageal epithelium remains unknown
We show for the first time that H1R, H2R, and H4R, but not H3R, are expressed in human esophageal epithelial biopsies, and their expression is induced in the setting of active inflammation in EoE

Summary

Introduction

Eosinophilic esophagitis (EoE) is a chronic food antigen-mediated disease characterized by eosinophil infiltration into the esophageal epithelium [1]. EoE is evolving as one of the most common causes of chronic esophagitis in children and adults, with recent incidence estimates of 56.7 per 100,000 and up to 50.5 per 100,000 in children [2]. Though the diagnostic hallmark of EoE is the infiltration of eosinophils into the esophageal epithelium, recent studies have highlighted the potential importance of other cell types including mast cells [5] and basophils [6] suggesting that accumulation of eosinophils into the esophageal epithelium may represent a final common pathway in EoE pathobiology. Increased mast cell burden associated with EoE has been shown to respond to treatments including topical steroids [7] and food elimination diets [8]. Treatment of pediatric EoE patients with anti-IL5 monoclonal antibody, mepolizumab, led to a reduction in esophageal eosinophilia, as well and significant reduction in mast cells [9]

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