Neutrophil death-more than meets the eye

Neutrophils play an indispensable role in the innate immune system as the body's first line of defense against pathogens. These highly specialized cells are rapidly recruited to infection sites, where they execute a variety of critical functions essential for pathogen clearance. These functions include phagocytosis, degranulation, the release of antimicrobial peptides and reactive oxygen species (ROS), as well as the formation of neutrophil extracellular traps (NETs), which serve to directly neutralize pathogens or restrict their spread. Despite their abundance-accounting for 40%-70% of total white blood cells in human circulation, neutrophils have a relatively short lifespan. To maintain immune homeostasis, approximately 1 billion neutrophils per kilogram of body weight are produced and cleared each day, a highly regulated and energy-intensive process. Neutrophil death is a highly heterogeneous process, with neutrophils undergoing different forms of cell death depending on the stimuli, signaling, and microenvironment. Even during aging or cell death, neutrophils continue to exert significant effects on the immune landscape. In this review, we discuss the dynamics of neutrophil turnover during homeostasis and inflammation, the diversity of mechanisms governing their death, and the multifaceted roles of neutrophils in modulating the immune environment both during and after their demise.