Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview

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.

The definition of neutrophil extracellular traps and the concentration of short-chain fatty acids in salmonella-induced inflammation of the intestine against the background of vancomycin and Bacteroides fragilis

“…At present, the most studied model is suicidal netosis, which lasts for 2-4 hours. Its onset is characterized by neutrophil activation, through the recognition of pathogens, which leads to the induction of the NADPH oxidase (NOX) complex, through protein kinase C, and to an increase in cytosolic Ca + [21][22][23]. These cations serve as a co-factor for peptidyl-arginase deaminase 4 (PAD4) and a nuclear enzyme that deaminates histones, modifies amino acids, which leads to decondensation of chromatin and loss of positive charges necessary for the interaction of histones with DNA [24,25].…”

Interactions of Mycoplasma hyopneumoniae with extracellular traps

“…This mechanism is defined as phagocytosis and is key in dismantling attacks by invading pathogens. Once the pathogen is inside the phagosome, the vacuole fuses with a granule inside the neutrophil, which contain an arsenal of weapons including enzymes, antimicrobial peptides, and reactive oxygen species (ROS) that can decimate the captured pathogen(s) (34,35). The contents of these granules can also be released from the neutrophil into the extracellular environment in a second defensive mechanism called degranulation.…”

“…Ongoing research has provided an overwhelming amount of evidence on the negative relationship between NETs and autoimmune disorders with resulting undesired pathology in the host upon release of the extracellular traps (35,(39)(40)(41).…”

“…The diversity of these microorganisms challenges the innate immune system to be prepared on every possible front, which is why we see an extensive variety of defense mechanisms with participates in post-translational modifications of histones by hypercitrullination, both mediating the transition of chromatin from a condensed to a decondensed state (35,44). The functionality of PAD4 is reliant on calcium cofactors, making the increase of calcium ions due to ROS an important step in driving NETosis.…”

“…NETosis has been stimulated primarily by ligand binding to TLRs and binding of C3 to complement receptors or by platelet activation (35,48). In this pathway, the chromatin still decondenses, but in contrast to ROS-dependent NET formation, the nuclear contents are trafficked to the cytoplasmic membrane and released into the environment without the disintegration of the nuclear membrane.…”