Coxsackie and Adenovirus Receptor (CAR) controls lung epithelial cell responses to inflammation

Abstract

Airway inflammation and remodeling are key features process in many respiratory conditions. An intact epithelial cell layer is crucial to maintain lung homeostasis, and this depends on intercellular adhesion, regulated by tight junctions and adherens junctions. The Coxsackie and adenovirus receptor (CAR) functions as a cell-cell adhesion molecule to stabilise epithelial cell-cell adhesions. CAR is also a receptor for immune cells and facilitates transepithelial migration (TEpM) after inflammation in the skin and gut. We have demonstrated that CAR is regulated through phosphorylation to control junction stability in lung epithelial cells and TEpM of monocytes and neutrophils in vitro and in inflammation in vivo. Here, we investigate the mechanistic role of CAR in mediating responses to the common aeroallergen House dust mite (HDM). We demonstrate that in vitro HDM treatment of bronchial epithelial cells leads to destabilisation of cell-cell adhesions, increased cell permeability and that this require HDM-dependent CAR phosphorylation. 5 weeks administration of HDM in mice lacking CAR in the respiratory epithelium leads to loss of peribronchial inflammatory cell infiltration(of neutrophils and γδT cells) in the lungs and decreased IL-4 and IL-13. Further analysis revealed the release of HDM-dependent inflammatory cytokines by the epithelium is regulated by CAR. Depletion of CAR reduces collagen I, fibronectin and a-SMA deposition in the lungs following HDM insult. Moreover, removal of CAR leads to increased contractility of the airways and CAR-dependent secretion from the epithelium results in enhanced airway smooth muscle cell proliferation. Our data demonstrates that CAR is a novel central co-ordinator of lung inflammation and may represent a strong target for future treatments.