Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts

Abstract

Both canonical and non-canonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; therefore, they can be an attractive target for pharmaceutical management of severe asthma. Wnt/β-catenin signaling was shown to link early embryonic lung development impairment to later in life asthmatic airway remodeling. Here we explored the changes in Wnt signaling associated with asthma initiation and progression in epithelial and fibroblasts using a comprehensive approach based on in silico analysis and followed by in vitro validation. In summary, the in silico analysis showed that the bronchial epithelium of severe asthmatic patients showed a deranged balance between Wnt enhancer and Wnt inhibitors. A Th2-high phenotype is associated with upregulated Wnt-negative regulators, while inflammatory and neutrophilic severe asthmatics showed higher canonical Wnt signaling member enrichment. Most of these genes are regulators of healthy lung development early in life and, if disturbed, can make people susceptible to developing asthma early in life and prone to developing a severe phenotype. Most of the Wnt members are secreted, and their effect can be in an autocrine fashion on the bronchial epithelium, paracrine on nearby adjacent structural cells like fibroblasts and smooth muscles, or systemic in blood. Our results showed that canonical Wnt signaling is needed for the proper response of cells to proliferative stimuli, which puts cells under stress. Cells in response to this proliferative stress will activate the senescence mechanism, which is also dependent on Wnt signaling. Inhibition of Wnt signaling using FH535 inhibits both proliferation and senescence markers in bronchial fibroblasts compared to DMSO-treated cells. In fibroblasts from asthmatic patients, inhibition of Wnt signaling did not show that effect as the Wnt signaling is deranged besides other pathways that might be non-functional.

Transcriptome-Wide m6A Methylome and m6A-Modified Gene Analysis in Asthma

“…A GWAS of asthma symptoms in 1,246 children in the population of Salvador, Brazil, was carried out ( Costa et al, 2015 ); they found that BCL11A is associated with hematopoietic symptoms of asthma, and it may be related to its interaction with BCL 6 and participation in hematopoietic cell differentiation. In addition, in another study of severe asthma ( Hachim et al, 2021 ), they found that BCL11A was downregulated. MATK (megakaryocyte-associated tyrosine kinase) is a protein-coding gene too.…”

Differentially expressed microRNAs in peripheral blood cell are associated with downregulated expression of IgE in nonallergic childhood asthma

“…There is a deranged balance between Wnt enhancer and Wnt inhibitors in the bronchial epithelium of severe asthmatic patients. The Th2-high asthma phenotype is associated with upregulated Wnt-negative regulators, while higher canonical Wnt signaling enriched pathway are observed in both inflammatory and severe neutrophilic asthmatics 53 .…”

Aging-Related Mechanisms Contribute to Corticosteroid Insensitivity in Elderly Asthma

“…Interestingly, treatment with the corticosteroid dexamethasone reduced inflammation and remodeling in wild-type but not club cell-specific ITGB4 knockout mice [ 64 ]. While the airway epithelial SASP is not defined for asthma, recent studies reported altered WNT/β-Catenin signaling between bronchial epithelium and fibroblasts that increased fibroblast senescence and airway remodeling [ 65 ]. These data suggest that aging may negatively impact the airway epithelium and disruption to changes to adhesion and barrier integrity can promote senescence and persistent airway remodeling in asthma.…”