Pro-apoptotic polymers for neutrophil-induced inflammation modulation: from screening to therapeutic potential

Abstract

Human polymorphonuclear neutrophils (PMNs) are pivotal in the initiation and resolution of inflammation, playing an essential role in maintaining tissue homeostasis and facilitating repair. This study investigates how polymers influence PMNs apoptosis, a favourable step for the resolution of inflammation, identifying poly(arginine) containing 30 arginine subunits (PAR30) as a potent pro-apoptotic agent. Further mechanistic analysis suggests that PAR30 induces apoptosis predominantly through mitochondrial ROS production, which in turn activates caspases 3 and 7 through the intrinsic apoptotic pathway. Remarkably, PMNs treated with PAR30 exhibit enhanced recognition and phagocytosis by macrophages, suggesting an overall more efficient clearance of apoptotic cells. These findings underscore PAR30 potential as a therapeutic agent for modulating inflammatory processes by promoting PMNs apoptosis and improving macrophage-mediated efferocytosis. Moreover, preliminary exploration of PAR30 chemical modifications in order to enhance its intracellular penetration, suggests that the pro-apoptotic effect could be enhanced, as displayed by increased annexin-V staining mediated by thiolated-PAR30. PAR30-based compounds appear as novel anti-inflammatory agents, capable of promoting neutrophil apoptosis and enhancing macrophage-mediated clearance, paving the way for therapeutic applications in difficult-to-treat inflammatory diseases.