Peculiarities of cell death mechanisms in neutrophils

Abstract

Analyses of neutrophil death mechanisms have revealed many similarities with other cell types; however, a few important molecular features make these cells unique executors of cell death mechanisms. For instance, in order to fight invading pathogens, neutrophils possess a potent machinery to produce reactive oxygen species (ROS), the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Evidence is emerging that these ROS are crucial in the execution of most neutrophil cell death mechanisms. Likewise, neutrophils exhibit many diverse granules that are packed with cytotoxic mediators. Of those, cathepsins were recently shown to activate pro-apoptotic B-cell lymphoma-2 (Bcl-2) family members and caspases, thus acting on apoptosis regulators. Moreover, neutrophils have few mitochondria, which hardly participate in ATP synthesis, as neutrophils gain energy from glycolysis. In spite of relatively low levels of cytochrome c in these cells, the mitochondrial death pathway is functional. In addition to these pecularities defining neutrophil death pathways, neutrophils are terminally differentiated cells, hence they do not divide but undergo apoptosis shortly after maturation. The initial trigger of this spontaneous apoptosis remains to be determined, but may result from low transcription and translation activities in mature neutrophils. Due to the unique biological characteristics of neutrophils, pharmacological intervention of inflammation has revealed unexpected and sometimes disappointing results when neutrophils were among the prime target cells during therapy. In this study, we review the current and emerging models of neutrophil cell death mechanisms with a focus on neutrophil peculiarities.

Figure 1

ROS-mediated neutrophil cell death. Upon exposure of neutrophils to various stimuli (e.g. bacteria, TNF-α or GM-CSF + fMLF), the NADPH oxidase is assembled at cellular and granular membranes and becomes activated. This activation results in extracellular and intracellular ROS generation. Depending on the level and – likely also – localization of ROS produced by the NADPH oxidase, neutrophils may die by apoptosis or necrosis, but may also show increased survival

Figure 2

Molecular mechanisms of neutrophil apoptosis. Neutrophils use different molecular pathways for the execution of apoptosis. Although spontaneous and FAS-induced apoptosis are heavily dependent on the mitochondrial death pathway, TNF-α- and endocytosis-induced apoptosis were shown to be mediated by ROS generation

Figure 3

Potential drug strategies to induce neutrophil apoptosis. Various points of attack can be envisioned to pharmacologically induce neutrophil apoptosis. Although some of the strategies would interfere with molecular pathways in many different cell types, others may target specifically neutrophils. It should be noted that under conditions of neutropenia, increased neutrophil survival might be the therapeutic goal (not shown)