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Smooth-muscle-derived WNT5A augments allergen-induced airway remodelling and Th2 type inflammation.
- Source :
-
Scientific reports [Sci Rep] 2020 Apr 21; Vol. 10 (1), pp. 6754. Date of Electronic Publication: 2020 Apr 21. - Publication Year :
- 2020
-
Abstract
- Asthma is a heterogeneous disease characterized by chronic inflammation and structural changes in the airways. The airway smooth muscle (ASM) is responsible for airway narrowing and an important source of inflammatory mediators. We and others have previously shown that WNT5A mRNA and protein expression is higher in the ASM of asthmatics compared to healthy controls. Here, we aimed to characterize the functional role of (smooth muscle-derived) WNT5A in asthma. We generated a tet-ON smooth-muscle-specific WNT5A transgenic mouse model, enabling in vivo characterization of smooth-muscle-derived WNT5A in response to ovalbumin. Smooth muscle specific WNT5A overexpression showed a clear trend towards enhanced actin (α-SMA) expression in the ASM in ovalbumin challenged animals, but had no effect on collagen content. WNT5A overexpression in ASM also significantly enhanced the production of the Th2-cytokines IL4 and IL5 in lung tissue after ovalbumin exposure. In line with this, WNT5A increased mucus production, and enhanced eosinophilic infiltration and serum IgE production in ovalbumin-treated animals. In addition, CD4 <superscript>+</superscript> T cells of asthma patients and healthy controls were stimulated with WNT5A and changes in gene transcription assessed by RNA-seq. WNT5A promoted expression of 234 genes in human CD4 <superscript>+</superscript> T cells, among which the Th2 cytokine IL31 was among the top 5 upregulated genes. IL31 was also upregulated in response to smooth muscle-specific WNT5A overexpression in the mouse. In conclusion, smooth-muscle derived WNT5A augments Th2 type inflammation and remodelling. Our findings imply a pro-inflammatory role for smooth muscle-derived WNT5A in asthma, resulting in increased airway wall inflammation and remodelling.
- Subjects :
- Actins genetics
Actins immunology
Airway Remodeling genetics
Allergens administration & dosage
Animals
Asthma chemically induced
Asthma genetics
Asthma pathology
CD4-Positive T-Lymphocytes drug effects
CD4-Positive T-Lymphocytes pathology
Cell Movement
Eosinophils immunology
Eosinophils pathology
Female
Gene Expression Regulation
Humans
Immunoglobulin E biosynthesis
Interleukin-4 genetics
Interleukin-4 immunology
Interleukin-5 genetics
Interleukin-5 immunology
Interleukins genetics
Interleukins immunology
Lung drug effects
Lung pathology
Lymphocyte Activation drug effects
Mice
Mice, Transgenic
Muscle, Smooth chemistry
Muscle, Smooth pathology
Ovalbumin administration & dosage
Primary Cell Culture
Transgenes
Wnt-5a Protein genetics
Wnt-5a Protein pharmacology
Airway Remodeling immunology
Asthma immunology
CD4-Positive T-Lymphocytes immunology
Lung immunology
Muscle, Smooth immunology
Wnt-5a Protein immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 32317758
- Full Text :
- https://doi.org/10.1038/s41598-020-63741-x