Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality

Abstract

Neutrophil extracellular traps (NETs) are chromatin structures loaded with antimicrobial molecules. They can trap and kill various bacterial, fungal and protozoal pathogens, and their release is one of the first lines of defense against pathogens. In vivo, NETs are released during a form of pathogen-induced cell death, which was recently named NETosis. Ex vivo, both dead and viable neutrophils can be stimulated to release NETs composed of either nuclear or mitochondrial chromatin, respectively. In certain pathological conditions, NETs are associated with severe tissue damage or certain auto-immune diseases. This review describes the recent progress made in the identification of the mechanisms involved in NETosis and discusses its interplay with autophagy and apoptosis. Cell Death and Differentiation (2011) 18, 581-588; doi:10.1038/cdd.2011.1; published online 4 February 2011Neutrophils have an essential role in innate immunity and are the first cells recruited to the site of infection.1 Human neutrophils are the most abundant leukocytes. They have a very short lifespan, and neutrophil homeostasis is maintained by continuous release of many neutrophils from the bone marrow. Accelerated neutrophil death decreases neutrophil counts (neutropenia) and increases susceptibility to infection. In turn, delayed neutrophil death increases neutrophil counts (neutrophilia) and intensifies innate defenses, possibly promoting chronic inflammation.2 Neutrophils perform their function by engulfing microorganisms or opsonized particles and degrading them by various molecules, and also release lytic enzymes that destroy extracellular pathogens.3 Moreover, they release structures called neutrophil extracellular traps (NETs) that can trap and kill microbes. 4 The neutrophil lifespan constitutes a sensitive balance between their function as effecter cells and their potential to inflict tissue damage. In the absence of inflammatory stimuli, neutrophils continuously undergo apoptosis within 24-48 h both in vivo and in cell culture. The large amounts of superoxide produced by the membrane-associated NADPH oxidase in neutrophils have a central role in the destruction of invading pathogens as well as in the resolution of inflammation. [5][6][7][8][9] Congenital defects that prevent NADPH oxidase activity result in chronic granulomatous disease (CGD), which is characterized by exaggerated immune responses 10 and recurrent life-threatening infections by a narrow set of microorganisms. 11 We recently found that formation of NETs by activated neutrophils requires not only NADPH-oxidasemediated superoxide production, but also autophagy. 12In this review, we present an overview of the main biochemical and morphological features observed during neutrophil activation and discuss in more detail the contribution of NADPH oxidase, histone citrullination, intracellular calcium levels and autophagy to chromatin decondensation and NET formation. Release of Extracellular TrapsIn 2004, the group of Brinkman and Zychlinsky was the first to report the rele...

La mort cellulaire programmée ne manque pas de vocabulaire

“…Elle a été nommée ainsi car elle a été initiallement observée dans des cellules sécrétant des pièges extracellulaires neutrophiles (NET), constitués de protéines antimicrobiennes, de chromatine nucléaire et d'histones [26]. Cette sécrétion se produit …”

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

“…160,162 Of note, ROS appear to be required but insufficient for netosis to occur, suggesting that the autophagic component of netosis cannot be entirely attributed to the autophagy-promoting activity of ROS. 160,163 Histone citrullination (i.e., the conversion of positively charged arginine side chains into polar, but uncharged citrulline side chains) also appears to participate in netosis by mediating chromatin decondensation and NET formation. 164 Thus, genetic inhibition of the major histone-citrullinating enzyme, that is, peptidylarginine deiminase 4 (PAD4), interfered with NET release by HL-60 cells stimulated with Ca 2 þ ionophores or Shigella flexneri.…”

“…In view of these observations, netosis might be defined as a cell death subroutine that is: (i) restricted to granulocytic cells; (ii) insensitive to (and perhaps dependent on) 163 caspase inhibition; (iii) insensitive to necrostatin; (iv) dependent on NAPDH oxidase-mediated superoxide generation; and (v) dependent on (components of) the autophagic machinery (Table 1). As it stands, netosis shares biochemical features with both autophagic cell death and regulated necrosis.…”

Neutrophil extracellular traps in bronchial aspirates: a quantitative analysis

“…In 2004, BRINKMANN et al [6] reported a newly identified neutrophil activity, which they called NETs [6]. NETs are produced by activated neutrophils in response to a variety of pro-inflammatory stimuli including lipopolysaccharide, interleukin (IL)-8, tumour necrosis factor (TNF), and various bacteria and fungi [7][8][9]. High mobility group box 1 (HMGB-1) was also recently reported to promote the formation of NETs [10].…”