Epithelial Coxsackievirus Adenovirus Receptor promotes house dust mite-induced lung inflammation

Elena Ortiz-Zapater, Virginia Llopis Hernandez, Dustin Bagley, Luke Roberts, Tom Maguire, Felizia Voss, Philipp Mertins, Marieluise Kirchner, Isabel Peset-Martin, Greg Woszczek, Jody Rosenblatt, Michael Gotthardt, George Santis, Madeline Parsons

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Airway inflammation and remodelling are important pathophysiologic features in asthma and other respiratory conditions. An intact epithelial cell layer is crucial to maintain lung homoeostasis, and this depends on intercellular adhesion, whilst damaged respiratory epithelium is the primary instigator of airway inflammation. The Coxsackievirus Adenovirus Receptor (CAR) is highly expressed in the epithelium where it modulates cell-cell adhesion stability and facilitates immune cell transepithelial migration. However, the contribution of CAR to lung inflammation remains unclear. Here we investigate the mechanistic contribution of CAR in mediating responses to the common aeroallergen, House Dust Mite (HDM). We demonstrate that administration of HDM in mice lacking CAR in the respiratory epithelium leads to loss of peri-bronchial inflammatory cell infiltration, fewer goblet-cells and decreased pro-inflammatory cytokine release. In vitro analysis in human lung epithelial cells confirms that loss of CAR leads to reduced HDM-dependent inflammatory cytokine release and neutrophil migration. Epithelial CAR depletion also promoted smooth muscle cell proliferation mediated by GSK3β and TGF-β, basal matrix production and airway hyperresponsiveness. Our data demonstrate that CAR coordinates lung inflammation through a dual function in leucocyte recruitment and tissue remodelling and may represent an important target for future therapeutic development in inflammatory lung diseases.

Original languageEnglish
Article number6407
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 27 Oct 2022

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