Elafin inhibits macrophage activation by blocking a chloride channel.

Abstract

The molecular mechanisms underlying the anti-inflammatory functions of elafin, beyond its role as a serine protease inhibitor, have garnered significant interest. In this study, we engineered an antibody-elafin fusion construct (Her-elafin) by grafting elafin into the complementarity-determining region (CDR) of the Herceptin antibody. Her-elafin retained the full inhibitory activity of elafin against neutrophil elastase and effectively suppressed lipopolysaccharide (LPS)-induced macrophage activation. Using Her-elafin as a molecular probe, we identified that elafin specifically binds to and inhibits Clic1, a chloride channel expressed on macrophages. This binding likely reduces intracellular reactive oxygen species (ROS) production, thereby attenuating downstream inflammatory cascades. Furthermore, the dual inhibitory activities of Her-elafin against neutrophil elastase and Clic1 resulted in significant anti-inflammatory effects in a murine model of acute lung injury, highlighting its potential as a promising therapeutic strategy.