The role of neutrophil death in chronic inflammation and cancer

Abstract

The lifespan of a neutrophil is short and limited by programmed cell death, followed by efferocytosis. When activated or exposed to insult, neutrophil death may be delayed to support neutrophil effector functions such as phagocytosis, cytokine release, and pathogen destruction by degranulation. However, neutrophils may also alter the type of cell death and thereby affect inflammatory responses and tissue remodeling. This review briefly introduces the various forms of neutrophil death including apoptosis, necrosis/necroptosis, and the formation of so-called “neutrophil extracellular traps” (NETs), and it summarizes the clearance of dead cells by efferocytosis. Importantly, distinct types of neutrophil death have been found to drive chronic inflammatory disorders and cancer. Thus, the tumor and its microenvironment can delay neutrophil apoptosis to exploit their pro-angiogenic and pro-metastatic properties. Conversely, neutrophils may enter rapid and suicidal cell death by forming extracellular traps, which are expelled DNA strands with neutrophil proteins. Components of these DNA–protein complexes such as histones, high-mobility group protein B1, or neutrophil elastase have been found to promote cancer cell proliferation, adhesion, migration, invasion, and thereby tumor metastasis. In other settings of chronic inflammatory disease such as gout, NETs have been found protective rather than detrimental, as they promoted the local degradation of pro-inflammatory cytokines by neutrophil proteases. Thus, the interaction of neutrophils with the tissue environment extends beyond the stage of the living cell and the type of neutrophil death shapes immune responses and tissue remodeling in health and disease.