Type 2 inflammation drives an airway basal stem cell program through insulin receptor substrate signaling.
Basal cell
IL-13
IL-4
airway inflammation
airway stem cell
asthma
basal cell adhesion molecule
chronic rhinosinusitis with nasal polyposis
single-cell RNA sequencing
type 2 inflammation
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:
06 2023
06 2023
Historique:
received:
01
06
2022
revised:
17
01
2023
accepted:
26
01
2023
medline:
9
6
2023
pubmed:
23
2
2023
entrez:
22
2
2023
Statut:
ppublish
Résumé
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown. We sought to determine the role of T2 cytokines in regulating airway BCs. Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration. Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63 These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.
Sections du résumé
BACKGROUND
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown.
OBJECTIVE
We sought to determine the role of T2 cytokines in regulating airway BCs.
METHODS
Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration.
RESULTS
Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63
CONCLUSIONS
These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.
Identifiants
pubmed: 36804595
pii: S0091-6749(23)00211-7
doi: 10.1016/j.jaci.2023.01.030
pii:
doi:
Substances chimiques
Receptor, Insulin
EC 2.7.10.1
Interleukin-13
0
Interleukin-4
207137-56-2
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
1536-1549Subventions
Organisme : NIAID NIH HHS
ID : R01 AI134989
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI095219
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI175149
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI078908
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI134989
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL120952
Pays : United States
Informations de copyright
Copyright © 2023. Published by Elsevier Inc.