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Review
。 2017 Feb 6;8:81.
doi: 10.3389/fimmu.2017.00081. eCollection 2017.

中性粒细胞胞外陷阱及其含义s in Inflammation: An Overview

Vidal Delgado-Rizo1, Marco A Martínez-Guzmán1, Liliana Iñiguez-Gutierrez1, Alejandra Garcia-Orozco1, Anabell Alvarado-Navarro1, Mary Fafutis-Morris1
Affiliations
Free PMC article
Review

中性粒细胞胞外陷阱及其含义s in Inflammation: An Overview

Vidal Delgado-Rizoet al. Front Immunol。 。
Free PMC article

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.

Keywords:NETs; autoinflammatory diseases; autoinmmune diseases; infectious diseases; metabolic diseases.

Figures

Figure 1
Figure 1
Sequential steps of suicidal NETosis。(1) Recognition of stimuli through receptors. (2) Activation of Raf/MEK/ERK kinases pathway and increase of cytosolic calcium that leads to gp91phox phosphorylation for activation of oxidase NADPH complex and subsequent reactive oxygen species (ROS) production. (3) Elastase and myeloperoxidase (MPO) translocation to nucleus from azurophil granules promoted by ROS and other yet unknown factors. Decondensation of chromatin and loss of the lobular shape of the nucleus. (4) Loss of nuclear and granular membrane, association of decondensed chromatin to cytoplasmic components. (5) Loss of plasmatic membrane and release of DNA as extracellular traps.
Figure 2
Figure 2
Sequential steps of vital NETosis。(1) Recognition of stimuli through receptors. (2) Loss of the lobular and multinucleated shape of the nucleus. (3, 4) Separation of external and internal nuclear membranes and budding of vesicles. (5) Vesicles in cytoplasm containing DNA filaments in form of pearl strings, approaching of dense cytoplasmic granules toward intact plasmatic membrane. (6) Release of DNA as extracellular traps released through a small area in cell surface; some cytoplasmic granules also fuse to plasmatic membrane and are released into extracellular space to associate with DNA.
Figure 3
Figure 3
Neutrophil extracellular traps (NETs) formation in psoriatic plaques。Psoriatic lesions in patients are originated after injuries in skin, which induce keratinocytes to release proinflammatory cytokines and antimicrobial peptides. Such molecules, like cathelicidin LL37, form complexes upon binding to DNA that activate plasmacytoid dendritic cells (pDCs) through interaction with toll-like receptor 9 (TLR9), leading them to secrete interferon alpha (IFN-α) and tumor necrosis factor alpha (TNF-α). These cytokines regulate dermal dendritic cells (dDCs) activation, which migrate to regional lymphoid nodes to present autoantigens to naïve CD4 T (Th0) cells. Subsequently, T cells differentiate into T helper 1 (Th1) or Th17 and migrate toward dermis, where they secrete IL-2, IFN-γ, TNF-α, IL-22, and IL-17 that contribute to recruitment and activation of macrophages, dDCs, and mast cells. These cells synthesize IL-23 and interleukin 1 beta (IL-1β) and thus induce release of mast cell extracellular traps (MCETs). Consequently, mast cells intracellular content is released along with IL-17 and other cytokines, which induce neutrophil infiltration into epidermis and formation of Munro’s microabscesses. Neutrophils encounter high concentrations of IL-23 and IL-1β in this microenvironment, which turn them susceptible to release NETs. Through NETs formation, they too secrete cellular contents including IL-17, thus amplifying the inflammatory process and increasing cells recruitment and keratinocytes activation. Finally, NETs are important sources of LL37–DNA complexes and IL-17, both of which activate pDCs and keratinocytes that, in turn, produce IFN-α and LL37, respectively. Th1 cells induce activation of T CD8 IL-17-producing cells in epidermis and pDCs within dermis, perpetuating the inflammatory environment in psoriatic lesions.
Figure 4
Figure 4
Pathogenesis of systemic erythematosus lupus。(1) Low-density granulocytes (LDGs) undergo apoptosis and release reactive oxygen species (ROS) and autoantigens, thus stimulating formation of neutrophil extracellular traps (NETs) as well as release of both antimicrobial peptides (AMPs) and nucleic acids (DNA, RNA). Nucleic acids and AMPs form complexes capable of binding to high-mobility group box 1 (HMGB1) protein, which can be recognized by toll-like receptors in plasmacytoid dendritic cells (pDCs), which respond by synthesizing interferon alpha (IFN-α), thus promoting formation of NETs and IL-6. Both cytokines induce differentiation of autoantibody-secreting autoreactive B cells, leading to formation of immune complexes that activate the complement system and also are susceptible to be internalized by pDCs through type II Fcγ receptors (FcγRII)-mediated endocytosis. Endosomes associate to toll-like receptors (TLRs)-containing vesicles, which results in activation of pDCs and synthesis of IFN-α, further inducing NETs and tissular inflammation. In addition, necrotic cells-derived DNA–HMGB1 complexes activate B cells resulting in production of autoantibodies and formation of immune complexes that activate pDCs, leading to IFN-α synthesis and thus establishing a positive feedback. (2) Another pathway capable of inducing autoantibodies production is mediated by release of autoantigens from apoptotic cells that undergo secondary necrosis and generate secondary necrotic cells (SNECs); accumulation of such cells in germinal centers of secondary lymphoid organs facilitates presentation of autoantigens by follicular dendritic cells (fDCs) to autoreactive B cells and subsequent formation of immune complexes that lead to persistent inflammatory process that causes tissular injury in SEL patients.
Figure 5
Figure 5
Neutrophil extracellular traps (NETs) aliviate inflammation caused by monosodium urate (MSU) crystals。密歇根州立大学晶体由precipit沉积在关节ation and by shedding from tophus and further ingested by phagocytes such as dendritic cells and macrophages. As a consequence, the increased intracellular concentration of sodium induces cells to enhance water uptake, thus diluting potassium below inflammasome-activation concentration threshold. IL-18 and IL-1β are secreted and mediate recruitment of neutrophils to inflamed joints; neutrophils further increase IL-1b levels by cleaving pro-IL-1b in a process mediated by proteinase 3 (PR3). Upon ingesting MSU crystals, neutrophils undergo NETosis that not only degrades MSU but also encapsulates it, effectively reducing its inflammatory potential. Finally, aggregates of NETs (aggNETs) further stop inflammation by degradingin situcytokines. In time, aggNETs may lead to new tophi formation.
Figure 6
Figure 6
High glucose primes neutrophils to undergo NETosis。Neutrophils in response to inflammatory stimuli [ionomycin, phorbol-12-myristate-13-acetate (PMA), or lipopolysaccharide (LPS)] generate oxidative stress in addition to producing cytokines such as IL-6 and tumor necrosis factor alpha (TNF-α) is triggered by high glucose in type 2 diabetes.
Figure 7
Figure 7
Neutrophil extracellular traps (NETs) and adipose tissue。(A)Obesity is characterized by an increase in adipose tissue and chronic low-grade inflammation in which adipocytes secrete adipokines, such as tumor necrosis factor alpha (TNF-α), IL-6, and IL-8, which have been associated with increased activity of peripheral neutrophils (generation of superoxide and induction of NETosis).(B)In mice under a high-fat diet (HFD), an increase in neutrophil recruitment is observed in adipose tissue and neutrophil elastase (NE) activity, consequently, it is possible that neutrophils may be promoting the insulin resistance through the degradation of insulin receptor substrate-1 (IRS-1).
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