Regulation of human neutrophil apoptosis and lifespan in health and disease

Abstract

Neutrophils (also called polymorphonuclear leukocytes, PMNs) are the most abundant white blood cells in humans and play a central role in innate host defense. Another distinguishing feature of PMNs is their short lifespan. Specifically, these cells survive for less than 24 hours in the bloodstream and are inherently pre-programed to die by constitutive apoptosis. Recent data indicate that this process is regulated by intracellular signaling and changes in gene expression that define an "apoptosis differentiation program." Infection typically accelerates neutrophil turnover, and as such, phagocytosis-induced cell death (PICD) and subsequent clearance of the corpses by macrophages are essential for control of infection and resolution of the inflammatory response. Herein we reprise recent advances in our understanding of the molecular mechanisms of neutrophil apoptosis with a focus on regulatory factors and pathway intermediates that are specific to this cell type. In addition, we summarize mechanisms whereby perturbation of PMN death contributes directly to the pathogenesis of many infectious and inflammatory disease states.

Keywords: Bax; Mcl-1; PCNA; apoptosis differentiation program; caspases; constitutive apoptosis; extrinsic pathway; gene expression; intracellular signaling; intrinsic pathway; pathogen; phagocytosis-induced cell death.

Figure 1

Overview of the extrinsic, intrinsic, and phagocytosis-induced apoptotic pathways. The extrinsic pathway is initiated by ligation and clustering of plasma membrane death receptors leading to activation of caspase-8 and caspase-3. The intrinsic apoptotic pathway is initiated when the relative abundance of the proapoptotic Bcl-2 family members (Bax and Bak) exceeds that of their anti-apoptotic counterparts (Mcl-1 and A1), which allows Bax and Bak to oligomerize and form pores in the outer mitochondrial membrane. Release of cytochrome C into the cytosol is an essential signal for activation of caspase-9 upstream of caspase-3. The PICD pathway is driven by particle uptake and NADPH oxidase-derived ROS. Leakage of cathepsins from damaged azurophilic granules leads to death receptor-independent activation of caspase-8. In addition, cathepsin-driven activation of Bid and degradation of Mcl-1 favor mitochondrial disruption and intrinsic pathway activation. Additional details are provided in the text.

Figure 2

Pathogen manipulation of neutrophil apoptosis. Major control points of neutrophil apoptosis that are targeted by microbial pathogens are depicted in the upper panel. Organisms known to affect these steps are listed in the lower panels. MOMP, mitochondrial outer membrane permeabilty.