Targeting neutrophil extracellular traps in bacterial infections: mechanistic insights and translational perspectives

Neutrophil Extracellular Traps (NETs) are web-like structures composed of DNA fibers, histones, and granular proteins released by the neutrophils activated upon various stimuli. Recognized as a host immune defense mechanism, NETs also play a significant role in several diseases, especially in bacterial infections. Research indicates that excessive NET formation contributes to various pathological outcomes, including multiple organ dysfunction. Once activated, NETs generally remain in a hyperinflammatory phenotype. In this review, we delineate how bacterial pathogens both induce excessive NET formation, driving endothelial dysfunction, and evade NET-mediated antimicrobial defense. Here, we critically examine the signaling crosstalk between the NET formation with other cell death pathways, particularly focusing on the ROS-mediated PAD4-RIPK axis as well as the gasdermin-D mediated lytic signaling. Developing therapeutic strategies that target NET function presents significant challenges, requiring a balance between maintaining beneficial aspects and eliminating harmful effects. Given the rise in antimicrobial resistance, targeting host factors could lead to the development of more effective strategies. Together, this review explores the molecular mechanisms of NET formation, the paradoxical roles of NETs in different bacterial infections, their interplay with other cell death pathways, their impact on sepsis, and the exploration of different components of NETs as potential therapeutic candidates.