Disruption of E-cadherin in the airway led to dysplastic stressed cells and asthma-like phenotypes

Abstract

While E-cadherin is a known core component of the adherens junction, how it controls cell fate remains poorly understood. Here, we show that in the mouse airway, inactivation of E-cadherin in epithelial progenitor club cells, but not terminally differentiated ciliated cells, led to increased proliferation, goblet cell metaplasia, and immune infiltration, mimicking asthma phenotypes without exposure to allergen. Single-cell RNA sequencing identified a cellular stress signature in the mutant airway; a profile previously associated with dysplastic alveolar transitional cells in fibrotic lungs. Chemokine genes such as Cxcl17 are upregulated in the mutant airway both in vivo and when cultured in isolation, identifying an intrinsic ability of the epithelium to sense junction breach and launch immune defense. Inactivation of Il4ra in the mutant attenuated goblet cell metaplasia, but not immune recruitment. Together, these findings demonstrate that loss of E-cadherin leads to airway remodeling through both an epithelium-intrinsic mechanism and epithelium-immune crosstalk.

Keywords: E-cadherin; asthma; dysplastic alveolar transitional cells; immune response; lung epithelium.