Altered Esophageal Histamine Receptor Expression in Eosinophilic Esophagitis (EoE): Implications on Disease Pathogenesis

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.

The Immunologic Mechanisms of Eosinophilic Esophagitis

“…HR1 and HR4 are expressed in epithelial eosinophils from biopsies of patients with active EoE, while HR2 expression is present throughout the EoE inflamed tissue [86]. Interestingly, expression of HR2 is increased in patients with both active and inactive EoE compared to controls, suggesting that aberrant epithelial expression of HR2 may predispose individuals to the development of EoE [86]. Further investigation is needed to better elucidate the pathophysiologic implications of these observations and to determine whether antihistamines or other targeted therapies may be beneficial in the treatment of EoE.…”

Recent advances in the pathological understanding of eosinophilic esophagitis

“…Histamine stimulation of esophageal epithelial cells in vitro has been shown to induce GM-CSF, TNF, and IL-8. These effects were inhibited by HR1 antagonists, but not HR2 anatgonists 62 . The effect of mast cell derived factors on epithelial function is currently unknown.…”

Human eosinophils and mast cells: Birds of a feather flock together

“…Histamine is another MC‐produced mediator that stimulates eosinophil recruitment through histamine GPCRs . For eosinophils, histamine can act as a chemoattractant through H1R and inhibit chemotaxis through H2R (when histamine concentration is high) .…”

“…MC‐expressed H4R regulates calcium mobilization and release of inflammatory mediators . Studies in mice found that antagonism of H4R resulted in inhibition of IgE‐induced upregulation of FcεRI, suggesting that H4R regulates FcεRI expression and function . H4R antagonists have been shown to reduce histamine‐mediated pruritusin AD patients .…”

“…162 Histamine is another MC-produced mediator that stimulates eosinophil recruitment through histamine GPCRs. 163 For eosinophils, histamine can act as a chemoattractant through H1R 164 and inhibit chemotaxis through H2R (when histamine concentration is high). 165 Histamine also influences eosinophil adhesion, Ca 2+ mobilization and cytoskeleton rearrangement via H4R.…”