Abstract
In addition to physical barriers, neutrophils are considered a part of the first line of immune defense. They can be found in the bloodstream, with a lifespan of 6–8 h, and in tissue, where they can last up to 7 days. The mechanisms that neutrophils utilize for host defense are phagocytosis, degranulation, cytokine production, and, the most recently described, neutrophil extracellular trap (NET) production. NETs are DNA structures released due to chromatin decondensation and spreading, and they thus occupy three to five times the volume of condensed chromatin. Several proteins adhere to NETs, including histones and over 30 components of primary and secondary granules, among them components with bactericidal activity such as elastase, myeloperoxidase, cathepsin G, lactoferrin, pentraxin 3, gelatinase, proteinase 3, LL37, peptidoglycan-binding proteins, and others with bactericidal activity able to destroy virulence factors. Three models for NETosis are known to date. (a) Suicidal NETosis, with a duration of 2–4 h, is the best described model. (b) In vital NETosis with nuclear DNA release, neutrophils release NETs without exhibiting loss of nuclear or plasma membrane within 5–60 min, and it is independent of reactive oxygen species (ROS) and the Raf/MERK/ERK pathway. (c) The final type is vital NETosis with release of mitochondrial DNA that is dependent on ROS and produced after stimuli with GM-CSF and lipopolysaccharide. Recent research has revealed neutrophils as more sophisticated immune cells that are able to precisely regulate their granular enzymes release by ion fluxes and can release immunomodulatory cytokines and chemokines that interact with various components of the immune system. Therefore, they can play a key role in autoimmunity and in autoinflammatory and metabolic diseases. In this review, we intend to show the two roles played by neutrophils: as a first line of defense against microorganisms and as a contributor to the pathogenesis of various illnesses, such as autoimmune, autoinflammatory, and metabolic diseases.
Highlights
Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology
Three models for NETosis are known to date. (a) Suicidal NETosis, with a duration of 2–4 h, is the best described model. (b) In vital NETosis with nuclear DNA release, neutrophils release neutrophil extracellular trap (NET) without exhibiting loss of nuclear or plasma membrane within 5–60 min, and it is independent of reactive oxygen species (ROS) and the Raf/MERK/ERK pathway. (c) The final type is vital NETosis with release of mitochondrial DNA that is dependent on ROS and produced after stimuli with GM-CSF and lipopolysaccharide
Suicidal NETosis, with a duration of 2–4 h, is the best described model [14], even though its molecular processes are not fully understood [15]. It starts with the activation of neutrophils through the recognition of stimuli, leading them to package and activate the NADPH oxidase (NOX) complex through protein kinase C (PKC)/Raf/MERK/ERK, as well as to increase cytosolic Ca++; these cations act as cofactors for peptidyl arginase deaminase 4 (PAD4), a nuclear enzyme that promotes the deamination of histones, modifying amino acids to allow the decondensation of chromatin by promoting the loss of the positive charges necessary for the interaction of histones with DNA [16, 17]
Summary
The mechanisms that neutrophils undertake for host defense are phagocytosis, degranulation, cytokine production, and, the most recently described, neutrophil extracellular traps (NETs) production [3]. Suicidal NETosis, with a duration of 2–4 h, is the best described model [14], even though its molecular processes are not fully understood [15] Stepwise, it starts with the activation of neutrophils through the recognition of stimuli, leading them to package and activate the NADPH oxidase (NOX) complex through protein kinase C (PKC)/Raf/MERK/ERK, as well as to increase cytosolic Ca++; these cations act as cofactors for peptidyl arginase deaminase 4 (PAD4), a nuclear enzyme that promotes the deamination of histones, modifying amino acids to allow the decondensation of chromatin by promoting the loss of the positive charges necessary for the interaction of histones with DNA [16, 17]. In vital NETosis, neutrophils release NETs without exhibiting a loss of nuclear or plasma membrane within 5–60 min, and it occurs independently of ROS and the Raf/MERK/ERK pathway This process consists of the release of nuclear DNA through three morphological changes: (a) nuclear envelope growth and vesicle release, (b) nuclear decondensation, and (c) nuclear envelope disruption [14, 22,23,24]. It is important to highlight highmobility group box 1 (HMGB1) protein-expressing platelets as major endogenous inducers of NET formation, during infectious processes and in sterile inflammation [31, 32]
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