Unraveling NETosis: From Immune Mechanisms to Therapeutic Innovations

Abstract

Neutrophil Extracellular Traps (NETs) are integral to immune responses, serving both protective and pathological roles in inflammatory diseases. Despite increasing recognition of NETs, significant gaps remain in understanding the nuanced mechanisms of NETosis and its implications for health and disease. This review systematically explores NETosis—the formation of NETs—by elucidating the molecular signaling pathways and cellular mechanisms involved. We highlight the distinction between classical suicidal NETosis and vital NETosis, providing detailed discussion of key regulatory molecules and events, including the roles of reactive oxygen species (ROS) and peptidyl arginine deiminase 4 (PAD4). Furthermore, we analyze the dual nature of NETosis: its protective role in pathogen clearance versus its contribution to tissue damage and autoimmunity. We examine regulatory influences of environmental factors, cytokines, and pathogens on NET formation. Finally, we discuss emerging therapeutic strategies targeting NETosis, focusing on inhibition of essential molecular components responsible for NET formation and the potential repurposing of existing therapies. This comprehensive review enhances understanding of NETosis mechanisms and their pathophysiological implications, ultimately guiding future research and therapeutic interventions across various inflammatory and autoimmune disorders.