Neutrophils

Neutrophils are the most abundant leukocyte population in

peripheral blood and have a lifespan of as little as 4 h in the circulation; this short half-life is balanced by continuous and tightly

regulated release from the bone marrow. Neutrophils are among

the first line of defense against invading microbes (Kobayashi and

Deleo, 2009), targeting pathogens through diverse mechanisms

including phagocytosis, reactive oxygen species (ROS) generation, the release of microbicidal molecules from cytoplasmic

granules, and the recently described extrusion of an extracellular chromatin meshwork—so-called NETosis (Brinkmann et al.,

2004).

In 2004, Brinkmann et al. described a distinct mechanism of

neutrophil cell death, resulting in the programmed externalization of a meshwork of chromatin fibers decorated with granulederived antimicrobial proteins (neutrophil extracellular traps or

NETs) (Brinkmann et al., 2004). NETosis has subsequently been

shown to be an important strategy by which neutrophils trap and

kill invading microorganisms (Brinkmann and Zychlinsky, 2012;

Kaplan and Radic, 2012). NETs can also damage the vasculature

and have the potential to trigger thrombosis (Fuchs et al., 2010;

Gupta et al., 2010; Brill et al., 2012; Saffarzadeh et al., 2012).

Although there is still much to learn regarding the triggers and signaling pathways that facilitate NETosis, important

roles have been suggested for the NADPH oxidase machinery

(Fuchs et al., 2007; Ermert et al., 2009; Bianchi et al., 2011;

Remijsen et al., 2011), ROS (Nishinaka et al., 2011; Palmer et al.,

2012), the Raf/mitogen-activated protein kinase/extracellular

signal-regulated kinase pathway (Hakkim et al., 2011), histone

citrullination (Neeli et al., 2008; Wang et al., 2009; Li et al.,

2010; Hemmers et al., 2011), MPO/neutrophil elastase (NE)

(Papayannopoulos et al., 2010; Metzler et al., 2011), autophagy

(Mitroulis et al., 2011; Remijsen et al., 2011), and microtubule

polymerization (Neeli et al., 2009). The characterization of pathways implicated in the development of NETs

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