Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps.
airway inflammation
airway stem cell
asthma
basal cell
basal cell adhesion molecule
bulk RNA-sequencing
chronic rhinosinusitis with nasal polyps
epithelial cell
interleukin-13
interleukin-4
single cell RNA-sequencing
type 2 inflammation
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
17 Oct 2023
17 Oct 2023
Historique:
pubmed:
31
10
2023
medline:
31
10
2023
entrez:
31
10
2023
Statut:
epublish
Résumé
The airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood. We hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation. Ethmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and Analysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and Together, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma.
Sections du résumé
Background
UNASSIGNED
The airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood.
Objective
UNASSIGNED
We hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation.
Methods
UNASSIGNED
Ethmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and
Results
UNASSIGNED
Analysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and
Conclusions
UNASSIGNED
Together, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma.
Identifiants
pubmed: 37904989
doi: 10.1101/2023.10.13.562288
pmc: PMC10614789
pii:
doi:
Types de publication
Preprint
Langues
eng
Déclaration de conflit d'intérêts
Conflict of Interest Statement: JAB has served on scientific advisory boards for Siolta Therapeutics, Third Harmonic Bio, Sanofi/Aventis. NAB has served on scientific advisory boards for Regeneron. KMB has served on scientific advisory boards for AstraZeneca, Regeneron, Sanofi and GlaxoSmithKline. TML has served on scientific advisory boards for Regeneron, Sanofi, Eli Lilly, and GlaxoSmithKline. JEG has served as a consultant for AstraZeneca. The rest of the authors declare that they have no relevant conflicts of interest.
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