Decreased expression of airway epithelial Axl is associated with eosinophilic inflammation in severe asthma.
Animals
Asthma
/ drug therapy
Eosinophils
/ metabolism
Granulocyte-Macrophage Colony-Stimulating Factor
/ genetics
Humans
Inflammation
/ metabolism
Mice
Proto-Oncogene Proteins
/ genetics
RNA, Messenger
/ metabolism
RNA, Small Interfering
Receptor Protein-Tyrosine Kinases
/ genetics
Axl Receptor Tyrosine Kinase
Airway
Asthma
Axl receptor tyrosine kinase
Eosinophilic inflammation
Granulocyte-macrophage colony-stimulating factor
Journal
Allergology international : official journal of the Japanese Society of Allergology
ISSN: 1440-1592
Titre abrégé: Allergol Int
Pays: England
ID NLM: 9616296
Informations de publication
Date de publication:
Jul 2022
Jul 2022
Historique:
received:
03
10
2021
revised:
17
02
2022
accepted:
26
02
2022
pubmed:
24
4
2022
medline:
6
7
2022
entrez:
23
4
2022
Statut:
ppublish
Résumé
Airway epithelium-derived cytokines are critical to provoke and perpetuate type 2 inflammation in asthma. Yet it is poorly understood how this epithelial cell-driven inflammatory response is negatively regulated. We previously reported that Axl receptor tyrosine kinase was expressed by basal cells in the airway epithelium and had a role in defining their stem cell identity. However, whether and how Axl regulates airway type 2 inflammation remains unknown. We performed immunofluorescence staining to compare Axl expression in airway epithelium between non-asthmatic subjects, mild-moderate asthma and severe asthma. We confirmed this result by interrogating public databases of global gene expression in endobronchial biopsies. We then quantified eosinophil numbers infiltrating into the trachea of wild-type or Axl-knockout mice that were intranasally treated with house dust mite extracts (HDM). Cell-based assays using siRNA targeting Axl were further performed to identify molecules involved in Axl-mediated regulation of inflammation. Histological assessments and transcriptome analyses revealed decreases in protein and mRNA of Axl in airway basal cells of severe asthmatics. This reduction of Axl expression was correlated with infiltration of eosinophils and mast cells in severe asthmatics. Eosinophil infiltration was more evident in the trachea of Axl-knockout mice in response to repetitive HDM administration. siRNA-mediated knockdown of Axl increased mRNA and protein expression of granulocyte macrophage-colony stimulating factor (GM-CSF) in human bronchial epithelial cells. Axl kinase expressed by basal cells may suppress excessive eosinophilic inflammation via inhibition of GM-CSF in the airway. Axl reduction has clinical implications for the pathogenesis of severe asthma.
Sections du résumé
BACKGROUND
BACKGROUND
Airway epithelium-derived cytokines are critical to provoke and perpetuate type 2 inflammation in asthma. Yet it is poorly understood how this epithelial cell-driven inflammatory response is negatively regulated. We previously reported that Axl receptor tyrosine kinase was expressed by basal cells in the airway epithelium and had a role in defining their stem cell identity. However, whether and how Axl regulates airway type 2 inflammation remains unknown.
METHODS
METHODS
We performed immunofluorescence staining to compare Axl expression in airway epithelium between non-asthmatic subjects, mild-moderate asthma and severe asthma. We confirmed this result by interrogating public databases of global gene expression in endobronchial biopsies. We then quantified eosinophil numbers infiltrating into the trachea of wild-type or Axl-knockout mice that were intranasally treated with house dust mite extracts (HDM). Cell-based assays using siRNA targeting Axl were further performed to identify molecules involved in Axl-mediated regulation of inflammation.
RESULTS
RESULTS
Histological assessments and transcriptome analyses revealed decreases in protein and mRNA of Axl in airway basal cells of severe asthmatics. This reduction of Axl expression was correlated with infiltration of eosinophils and mast cells in severe asthmatics. Eosinophil infiltration was more evident in the trachea of Axl-knockout mice in response to repetitive HDM administration. siRNA-mediated knockdown of Axl increased mRNA and protein expression of granulocyte macrophage-colony stimulating factor (GM-CSF) in human bronchial epithelial cells.
CONCLUSIONS
CONCLUSIONS
Axl kinase expressed by basal cells may suppress excessive eosinophilic inflammation via inhibition of GM-CSF in the airway. Axl reduction has clinical implications for the pathogenesis of severe asthma.
Identifiants
pubmed: 35459569
pii: S1323-8930(22)00034-X
doi: 10.1016/j.alit.2022.02.010
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins
0
RNA, Messenger
0
RNA, Small Interfering
0
Granulocyte-Macrophage Colony-Stimulating Factor
83869-56-1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Axl Receptor Tyrosine Kinase
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
383-394Informations de copyright
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