TY - JOUR
T1 - Epithelial Coxsackievirus Adenovirus Receptor promotes house dust mite-induced lung inflammation
AU - Ortiz-Zapater, Elena
AU - Llopis Hernandez, Virginia
AU - Bagley, Dustin
AU - Roberts, Luke
AU - Maguire, Tom
AU - Voss, Felizia
AU - Mertins, Philipp
AU - Kirchner, Marieluise
AU - Peset-Martin, Isabel
AU - Woszczek, Greg
AU - Rosenblatt, Jody
AU - Gotthardt, Michael
AU - Santis, George
AU - Parsons, Madeline
N1 - Funding Information:
The authors gratefully acknowledge funding from the Medical Research Council UK (MR/S009191/1 and R151002, both to M.P.), the DZHK (to M.G.) and MRC & Asthma UK Centre grant (G1000758) to G.W.). G.S. would like to thank the Biomedical Research Centre Guy’s & St Thomas’ NHS Foundation Trust and King’s College London and a grateful patient for financial support. We would also like to thank Ismael Ranz for assistance with FACS analysis, Dr Claudia Owczarek for assistance with tissue processing, Dr Mark Rigby (Nikon UK) for assistance with image analysis and Janine Fröhlich for support with the BioID experiments.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/10/27
Y1 - 2022/10/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85140799711&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-33882-w
DO - 10.1038/s41467-022-33882-w
M3 - Article
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6407
ER -