Protocadherin-1 deficiency increases baseline and allergen-induced airway hyperresponsiveness in mice.

Authors

Bao-Han Ly, Uilke Brouwer, Laura Hesse, Kuldeep Kumawat, Djoke van Gosliga, Arjen H Petersen, Susan Nijboer, Lisette E den Boef, Marnix R Jonker, Renske Karsenberg, Jelle R Dalenberg, Wim Timens, Janette K Burgess, Sarah A Teichmann, Antoon J M van Oosterhout, Bart N Lambrecht, Kerstin B Meyer, Frans van Roy, Tino Hochepied, Louis Bont, Jolanda van Hengel, Martijn C Nawijn, Gerard H Koppelman

Published in

American journal of respiratory cell and molecular biology. Jul 07, 2026. Epub Jul 07, 2026.

Abstract

Asthma is a heterogeneous airway disease characterized by chronic inflammation, airway hyperresponsiveness (AHR), and airway remodeling. Previously, we identified Protocadherin-1 (PCDH1) as a susceptibility gene for AHR, a hallmark of asthma. PCDH1 is an adhesion molecule, highly expressed in the airway epithelium. However, its role in AHR, airway inflammation, and remodeling is not fully understood. We generated Pcdh1-deficient mice to test whether Pcdh1 loss increases susceptibility to developing asthma features, including AHR, airway inflammation, and remodeling at baseline or upon challenge with house-dust mite (HDM) or Respiratory Syncytial Virus (RSV). Pcdh1-deficient mice were viable and expressed a truncated form of Pcdh1. Naive Pcdh1-knockout (KO) mice displayed lower lung compliance than wild-type (WT) littermate controls. The barrier integrity of cultured tracheal epithelial cells isolated from KO and HET was lower than that of WT mice. Intriguingly, single-cell RNA sequencing analysis of tracheal epithelial cells revealed higher proportions of basal cells and a unique Hillock-like cell population in KO mice, while ciliated cells were lower in proportion. Upon HDM exposure, but not RSV infection, Pcdh1-KO mice showed increased AHR and lower lung compliance compared to WT mice. Altogether, we demonstrate that Pcdh1 deficiency in mice results in loss of airway epithelial barrier integrity and reduced lung compliance at baseline and after HDM exposure, indicating a potential role in airway remodeling. These changes are accompanied by alterations in airway epithelial differentiation. In conclusion, this novel mouse model points towards a role of Protocadherin-1 in remodeling of the airways, epithelial differentiation and barrier integrity.

PMID:
42412517
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.

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