Modulatory effect of clusterin on dendritic cell recruitment in allergic airway inflammation

Abstract

Recruitment and activation of dendritic cells (DCs) in the lungs is critical for Th2 responses in asthma. CCL20 secreted from bronchial epithelial cells (BECs) influences the recruitment of DCs. Clusterin, an oxidative stress regulatory molecule, may play a pivotal role in the pathogenesis of allergic airway inflammation. The aim of this study was to examine if clusterin functions in the regulation of CCL20 production from BECs and is involved in allergic airway inflammation through DC recruitment. Clusterin knockout $(Clu^{-/-})$ mice were exposed to house dust mite (HDM) extract to induce allergic airway inflammation. We observed the effect of clusterin on the production of chemokines including CCL20, development of allergic airway inflammation, immune cell recruitment to the lung, and lipid peroxidation products as oxidative stress biomarkers. The number of total immune cells in bronchoalveolar lavage fluid (BALF) and the lung were dramatically increased in $Clu^{-/-}$ mice. Inflammatory DC $(CD11b^+CD11c^+)$ and $Ly6C^{high}$ monocytes populations in the lung were also significantly increased, which was accompanied by increased CCL20 expression in BALF and oxidative stress marker expression in the lung. Moreover, CCL20 and ROS generation were then evaluated in HDM-stimulated human BECs in the setting of clusterin overexpression and downregulation. HDM-stimulated clusterin up- and down-regulated BECs showed that CCL20 secretion was negatively correlated with clusterin expression. Clusterin attenuated intracellular ROS production, which is related to induction of CCL20 expression after HDM stimulation. Thus, the antioxidant effect of clusterin may modulate recruitment of DCs to the airway by regulating CCL20 production.