Single-Cell and Population Transcriptomics Reveal Pan-epithelial Remodeling in Type 2-High Asthma.
Asthma
/ genetics
Biological Transport
/ drug effects
Cellular Reprogramming
/ drug effects
Child
Cilia
/ drug effects
Down-Regulation
/ drug effects
Endoplasmic Reticulum Stress
/ drug effects
Epithelium
/ drug effects
Humans
Immunity, Innate
/ drug effects
Interferons
/ metabolism
Interleukin-13
/ pharmacology
Metaplasia
Mucus
/ metabolism
Single-Cell Analysis
Transcriptome
/ drug effects
GALA
RNA-seq
air-liquid interface
ciliary beat frequency
disease
lung
proteomics
secretome
single cell sequencing
type 2 inflammation
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
07 07 2020
07 07 2020
Historique:
received:
12
03
2020
revised:
14
05
2020
accepted:
15
06
2020
entrez:
9
7
2020
pubmed:
9
7
2020
medline:
29
4
2021
Statut:
ppublish
Résumé
The type 2 cytokine-high asthma endotype (T2H) is characterized by IL-13-driven mucus obstruction of the airways. To further investigate this incompletely understood pathobiology, we characterize IL-13 effects on human airway epithelial cell cultures using single-cell RNA sequencing, finding that IL-13 generates a distinctive transcriptional state for each cell type. Specifically, we discover a mucus secretory program induced by IL-13 in all cell types which converts both mucus and defense secretory cells into a metaplastic state with emergent mucin production and secretion, while leading to ER stress and cell death in ciliated cells. The IL-13-remodeled epithelium secretes a pathologic, mucin-imbalanced, and innate immunity-depleted proteome that arrests mucociliary motion. Signatures of IL-13-induced cellular remodeling are mirrored by transcriptional signatures characteristic of the nasal airway epithelium within T2H versus T2-low asthmatic children. Our results reveal the epithelium-wide scope of T2H asthma and present candidate therapeutic targets for restoring normal epithelial function.
Identifiants
pubmed: 32640237
pii: S2211-1247(20)30853-6
doi: 10.1016/j.celrep.2020.107872
pmc: PMC8046336
mid: NIHMS1610247
pii:
doi:
Substances chimiques
Interleukin-13
0
Interferons
9008-11-1
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
107872Subventions
Organisme : NHLBI NIH HHS
ID : U01 HL138626
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135156
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128439
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL132821
Pays : United States
Organisme : NIMHD NIH HHS
ID : R01 MD010443
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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