Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts.

Mahmood Yaseen Hachim,Saba Al Heialy,Ibrahim Yaseen Hachim,Rifat Hamoudi,Hauke Busch,Qutayba Hamid,Rakhee K Ramakrishnan,Noha Mousaad Elemam,Ronald Olivenstein,Khuloud Bajbouj

doi:10.3389/fcell.2021.641404

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.

Highlights

The hybrid name “WNT” stands for a group of genes belonging to the INT1 (WNT1)/wingless family (Pai et al, 2017)
Wnt signaling pathways maintain lung homeostasis, and any disturbance of such pathway can cause debilitating lung diseases (Rapp et al, 2017), like fibrosis (Burgy and Konigshoff, 2018), and asthmatic airway remodeling (Hussain et al, 2017). Both canonical and non-canonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; they can be an attractive target for pharmaceutical management of severe asthma (Baarsma and Konigshoff, 2017)
All the 35 genes identified earlier to be the top DEG in the bronchial epithelium were DEG between asthmatic and healthy bronchial fibroblasts as well. This highlights that those 35 genes represent DEGs in asthmatic airways irrespective of cell type

Summary

Introduction

The hybrid name “WNT” (for Wingless-related integration site) stands for a group of genes belonging to the INT1 (WNT1)/wingless family (Pai et al, 2017). Wnt signaling pathways maintain lung homeostasis, and any disturbance of such pathway can cause debilitating lung diseases (Rapp et al, 2017), like fibrosis (Burgy and Konigshoff, 2018), and asthmatic airway remodeling (Hussain et al, 2017). Both canonical and non-canonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; they can be an attractive target for pharmaceutical management of severe asthma (Baarsma and Konigshoff, 2017). Wnt/β-catenin signaling was shown to link early embryonic lung development impairment to later in life asthmatic airway remodeling (Hussain et al, 2017)

Methods

Results

Conclusion