Global assessment of the integrated stress response in CF patient-derived airway and intestinal tissues.
Adult
Bronchi
/ cytology
Cells, Cultured
Cystic Fibrosis
/ genetics
Cystic Fibrosis Transmembrane Conductance Regulator
/ genetics
Endoplasmic Reticulum Stress
/ genetics
Epithelial Cells
Female
Gene Expression Profiling
Humans
Immunity, Innate
Inflammation
Middle Aged
Organoids
Proof of Concept Study
Signal Transduction
Symptom Flare Up
Transcriptome
Cystic fibrosis
ER stress
F508del-CFTR
Inflammation
RNA-seq
Tissue remodeling
Unfolded protein response (UPR)
Journal
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
ISSN: 1873-5010
Titre abrégé: J Cyst Fibros
Pays: Netherlands
ID NLM: 101128966
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
16
01
2020
revised:
19
03
2020
accepted:
17
04
2020
pubmed:
27
5
2020
medline:
21
10
2021
entrez:
27
5
2020
Statut:
ppublish
Résumé
Chronic inflammation is a hallmark among patients with cystic fibrosis (CF). We explored whether mutation-induced (F508del) misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR), and/or secondary colonization with opportunistic pathogens, activate tissue remodeling and innate immune response drivers. Using RNA-seq to interrogate global gene expression profiles, we analyzed stress response signaling cascades in primary human bronchial epithelia (HBE) and intestinal organoids. Primary HBE acquired from CF patients with advanced disease and prolonged exposure to pathogenic microorganisms display a clear molecular signature of activated tissue remodeling pathways, unfolded protein response (UPR), and chronic inflammation. Furthermore, CFTR misfolding induces inflammatory signaling cascades in F508del patient-derived organoids from both the distal small intestine and colon. Despite the small patient cohort size, this proof-of-principle study supports the use of RNA-seq as a means to both identify CF-specific signaling profiles in various tissues and evaluate disease heterogeneity. Our global transcriptomic data is a useful resource for the CF research community for analyzing other gene expression sets influencing CF disease signature but also transcriptionally contributing to CF heterogeneity.
Sections du résumé
BACKGROUND
Chronic inflammation is a hallmark among patients with cystic fibrosis (CF). We explored whether mutation-induced (F508del) misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR), and/or secondary colonization with opportunistic pathogens, activate tissue remodeling and innate immune response drivers.
METHODS
Using RNA-seq to interrogate global gene expression profiles, we analyzed stress response signaling cascades in primary human bronchial epithelia (HBE) and intestinal organoids.
RESULTS
Primary HBE acquired from CF patients with advanced disease and prolonged exposure to pathogenic microorganisms display a clear molecular signature of activated tissue remodeling pathways, unfolded protein response (UPR), and chronic inflammation. Furthermore, CFTR misfolding induces inflammatory signaling cascades in F508del patient-derived organoids from both the distal small intestine and colon.
CONCLUSION
Despite the small patient cohort size, this proof-of-principle study supports the use of RNA-seq as a means to both identify CF-specific signaling profiles in various tissues and evaluate disease heterogeneity. Our global transcriptomic data is a useful resource for the CF research community for analyzing other gene expression sets influencing CF disease signature but also transcriptionally contributing to CF heterogeneity.
Identifiants
pubmed: 32451204
pii: S1569-1993(20)30118-1
doi: 10.1016/j.jcf.2020.04.005
pmc: PMC7932027
mid: NIHMS1672643
pii:
doi:
Substances chimiques
CFTR protein, human
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
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
1021-1026Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL151965
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK068196
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136414
Pays : United States
Informations de copyright
Copyright © 2020 European Cystic Fibrosis Society. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare no conflicts of interest.
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