Novel Signaling Function of hCLCA1 in Airway Macrophage Activation

The CLCA gene family produces both secreted and membrane-associated proteins that modulate ion-channel activity, drive mucus production and have a poorly understood pleiotropic effect on airway inflammation. The mechanism of how hCLCA1 regulates airway inflammation remains unknown. However, hCLCA1 induction in inflamed airway epithelium is higher than most cytokines and chemokines that activate resident and recruited macrophages’ innate immune response. Thus, it is possible that hCLCA1’s role in airway inflammation is to regulate the immune response of macrophages. Here, we demonstrated the ability of secreted hCLCA1 to activate macrophages, inducing them to express pro-inflammatory cytokines and to undertake a pivotal role in airway inflammation. The VWA domain within hCLCA1 was found to be responsible for the activation, which correlated with induction of the NF-κB and MAPK pathways. These findings open a new area of investigation into the function of CLCA proteins and should be of therapeutic interest