Asthma is characterized by reversible narrowing of the airways and airway obstruction, caused by inflammation, airway wall thickening and mucus production. Cells lining the airways, called epithelial cells, are thought to drive the development of asthma. When damaged, airway epithelial cells secrete signals called cytokines, such as CCL20 and GM-CSF, which attract and activate immune cells to induce airway inflammation. Airway epithelial cells form a tight barrier against the inhaled environment with the help of junction proteins, including E-cadherin and β-catenin. This barrier can be disrupted upon exposure to environmental insults such as house dust mite (HDM). E-cadherin is reduced in the airways of asthma patients, leading to loss of barrier function. Additionally, E-cadherin loss leads to the release of β-catenin into the cell, serving as signal to activate genes involved in inflammatory responses, airway wall remodelling and differentiation of epithelial cells towards mucus-producing cells. We hypothesized that activation of β-catenin signalling leads to abnormalities of airway epithelial cells as observed in asthma. To test this, we used small molecule inhibitor ICG-001 to specifically block β-catenin signalling. We cultured airway epithelial cells from asthma and healthy donors, exposed these to HDM, and studied the effect of ICG-001treatment. We found that ICG-001 improved airway epithelial barrier function, reduced the release of HDM-induced CCL20 and GM-CSF and inhibited differentiation towards mucus-producing cells. In a mouse model of asthma, ICG-001 also inhibited mucus production upon repeated HDM inhalation. Finally, we also observed that deletion of E-cadherin gene in mice was sufficient to cause spontaneous airway inflammation and did not further increase HDM-induced inflammation. In conclusion, we show that β-catenin signalling contributes to the development of asthma features and therefore, could be a novel target for therapeutic intervention.
|Kwalificatie||Doctor of Philosophy|
|Datum van toekenning||28-jun-2021|
|Plaats van publicatie||[Groningen]|
|Status||Published - 2021|