Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α.
Adolescent
Adult
Aged
Biomarkers
/ metabolism
Cells, Cultured
Child
Child, Preschool
Coculture Techniques
Constriction, Pathologic
Eosinophilic Esophagitis
/ diagnosis
Epithelial Cells
/ physiology
Esophagus
/ pathology
Female
Fibroblasts
/ physiology
Fibrosis
Gene Ontology
Humans
Infant
Male
Middle Aged
Protein-Lysine 6-Oxidase
/ genetics
Tumor Necrosis Factor-alpha
/ metabolism
Up-Regulation
Young Adult
Eosinophilic esophagitis
TGF-β
TNF-α
coculture
fibrosis
lysyl oxidase
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
13
03
2018
revised:
16
10
2018
accepted:
29
10
2018
pubmed:
24
12
2018
medline:
6
5
2020
entrez:
23
12
2018
Statut:
ppublish
Résumé
Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE. We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE. LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast-epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting. Gene ontology and pathway analyses linked TNF-α and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-α-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-α stimulates epithelial LOX expression through activation of nuclear factor κB and TGF-β-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE. There is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-α secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.
Sections du résumé
BACKGROUND
Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE.
OBJECTIVE
We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE.
METHODS
LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast-epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting.
RESULTS
Gene ontology and pathway analyses linked TNF-α and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-α-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-α stimulates epithelial LOX expression through activation of nuclear factor κB and TGF-β-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE.
CONCLUSIONS
There is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-α secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.
Identifiants
pubmed: 30578874
pii: S0091-6749(18)32772-6
doi: 10.1016/j.jaci.2018.10.067
pmc: PMC6586527
mid: NIHMS1519172
pii:
doi:
Substances chimiques
Biomarkers
0
Tumor Necrosis Factor-alpha
0
LOX protein, human
EC 1.4.3.13
Protein-Lysine 6-Oxidase
EC 1.4.3.13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
171-182Subventions
Organisme : NIDDK NIH HHS
ID : K01 DK103953
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK118310
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK118304
Pays : United States
Organisme : NIAID NIH HHS
ID : U54 AI117804
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES013508
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA098101
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK106444
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK100088
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA174176
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR001879
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK050306
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114436
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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