Regulated cell death in neutrophils: From apoptosis to NETosis and pyroptosis

Abstract

Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed tissues and play an essential role in host defense against infections. They exert microbicidal activity through a variety of specialized effector mechanisms, including phagocytosis, production of reactive oxygen species, degranulation and release of secretory vesicles containing broad-spectrum antimicrobial factors. In addition to their homeostatic turnover by apoptosis, recent studies have revealed the mechanisms by which neutrophils undergo various forms of regulated cell death. In this review, we will discuss the different modes of regulated cell death that have been described in neutrophils, with a particular emphasis on the current understanding of neutrophil pyroptosis and its role in infections and autoinflammation.

Keywords: Apoptosis; Cell death; Infection; Inflammation; Netosis; Neutrophil; Pyroptosis.

Fig. 1

Simplified scheme of neutrophil development, migration and activity. Neutrophils are produced in the bone marrow from hematopoietic stem cells (HSCs) and differentiate into mature neutrophils under the control of granulocyte-colony stimulating factor (G-CSF) and chemokines such as CXCL1, 2, 5 and 8. Mature neutrophils exit the bone marrow to patrol the circulation and migrate into tissues upon detection of microbial or inflammatory signals. At the site of inflammation, neutrophils deploy their arsenal of effector functions including phagocytosis, degranulation, ROS production and neutrophil extracellular trap (NET) formation.

Fig. 2

Schematic overview of apoptosis, ROS-induced NETosis and pyroptosis pathways in neutrophils. Apoptosis is a homeostatic and non-inflammatory mode of regulated cell death that is induced by apoptotic caspases and modulated by the expression levels of pro- and anti-apoptotic Bcl-2 family members. In contrast, ROS-induced NETosis and pyroptosis are lytic forms of regulated cell death in which plasma membrane permeabilization leads to leakage of intracellular proteins into the intracellular space. ROS-induced NETosis is associated with expulsion of neutrophils extracellular traps (NETs) following NADPH oxidase-induced ROS production and histone degradation by granule-released serine proteases. Pyroptosis is induced by GSDMD and GSDME pores in the plasma membrane following their cleavage by caspase-1, caspase-11 or ELANE (GSDMD) and caspase-3 (GSDME) in the stimulus-dependent signaling pathways depicted in the figure.