Altered esophageal histamine receptor expression in Eosinophilic Esophagitis (EoE): implications on disease pathogenesis.
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.
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Jamie
J
Merves
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Prasanna Modayur
PM
Chandramouleeswaran
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Alain J
AJ
Benitez
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Amanda B
AB
Muir
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Anna J
AJ
Lee
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Diana M
DM
Lim
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Kara
K
Dods
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Isha
I
Mehta
Division of Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Eduardo D
ED
Ruchelli
Department of Gastroenterology, Hepatology and Nutrition, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Hiroshi
H
Nakagawa
Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Jonathan M
JM
Spergel
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Mei-Lun
ML
Wang
D000293:Adolescent; D001706:Biopsy; D002452:Cell Count; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D057765:Eosinophilic Esophagitis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004804:Eosinophils / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007223:Infant; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D011968:Receptors, Histamine / Q000235:genetics* / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016209:Interleukin-8; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor