Matters of life and death. How neutrophils die or survive along NET release and is "NETosis" = necroptosis?

Abstract

Neutrophil extracellular trap (NET) formation is a hallmark of many disorders that involve neutrophil recruitment, tissue damage, and inflammation. As NET formation is often associated with neutrophil death, the term "NETosis" has become popular. Upon discovery that neutrophils may survive NET release, apparent misnomers, such as "vital NETosis," have been proposed. Meanwhile, it has become obvious that certain stimuli can trigger neutrophil necroptosis, a process associated with NET-like chromatin release. Here, we discuss the relationship between NET release and neutrophil death in view highlighting that many assays used in the field do not properly distinguish between the two. An updated nomenclature is needed replacing the term "NETosis" to meet the growing variety of settings leading to chromatin release with and without neutrophil death. Dissecting which triggers of NET release involve which signaling pathway will help to define drugable molecular targets that inhibit NET release and/or neutrophil necrosis in specific disorders.

Keywords: Gout; Histones; Host defense; Infection; Regulated necrosis; Sterile inflammation.

Fig. 1

Chromatin release as a consequence of neutrophil necroptosis. Stimuli-like monosodium urate (MSU) crystals and phorbol 12-myristate 13-acetate (PMA) induce activation of a receptor interacting protein kinase (RIPK)3- and mixed lineage kinase domain-like (MLKL)-dependent signaling pathway downstream of reactive oxygen species (ROS). This leads to plasma membrane rupture and NET-like chromatin release together with granular enzymes as a consequence at around 2 h of stimulation

Fig. 2

Neutrophil death and NET formation. Aging neutrophils die by apoptosis, whereas stimuli-like crystals, PMA, LPS, and TNF induce NET release associated with neutrophil death, referred to as necroptosis. Neutrophils are also known to release NETs without death, referred to as vital NET formation, upon certain bacterial stimuli, e.g., S. aureus. Inhibitors of necroptosis, e.g., RIPK1 and MLKL inhibitors as well as inhibitors of ROS, proteases, and PAD can block NET release associated with neutrophil death