Neutrophil Extracellular Traps In Diseases Research Articles

New insights in neutrophil extracellular traps: Its possible association in COVID-19 pathogenesis

Neutrophils discovered by Elie Metchnikoff are granulocytes that play a critical role as a first-line defense in innate immunity. They freely circulate in the blood vessels. Upon receiving the chemotactic gradient signal, neutrophils become the first white blood cells that get activated in various inflammatory sites, defending the human body from the microbial attack. The process of neutrophil extracellular traps (NETs) formation, through the neutrophil action mechanism, is a specific type of cell death, known as NETosis, distinct from necrosis and apoptosis. Oxidative burst mechanisms kill the pathogens trapped in NETs by two procedures – production of reactive oxygen species and chromatin unfolding. The mechanism of NETs draws an analog with the pathogenesis of periodontitis due to dysregulated neutrophilic response to specific bacterial species found in subgingival plaque. NETs are a fibrous structure that consists of a backbone of chromatin with attached globular domains. There are granular proteins and peptides in these domains as well as some cytoplasmic components. The core histones-A potent antimicrobials (H2A, H2B, H3, and H4) that together account for around 70% of the protein mass are the key component of the system. In this NETs-novel coronavirus disease-19 (nCOVID-19) intriguing centric overview, we have a mechanism for NET production; the ability of NETs to entrap and kill pathogens, including the potential immunogenicity of NETs in disease. We have also speculated a few comments on the possible role of NETs in the nCOVID-19.

Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging.

Peptidylarginine deiminase 4 (PAD4) is a nuclear citrullinating enzyme that is critically involved in the release of decondensed chromatin from neutrophils as neutrophil extracellular traps (NETs). NETs, together with fibrin, are implicated in host defense against pathogens; however, the formation of NETs (NETosis) has injurious effects that may outweigh their protective role. For example, PAD4 activity produces citrullinated neoantigens that promote autoimmune diseases, such as rheumatoid arthritis, to which PAD4 is genetically linked and where NETosis is prominent. NETs are also generated in basic sterile inflammatory responses that are induced by many inflammatory stimuli, including cytokines, hypoxia, and activated platelets. Mice that lack PAD4-deficient in NETosis-serve as an excellent tool with which to study the importance of NETs in disease models. In recent years, animal and human studies have demonstrated that NETs contribute to the etiology and propagation of many common noninfectious diseases, the focus of our review. We will discuss the role of NETs in thrombotic and cardiovascular disease, the induction of NETs by cancers and its implications for cancer progression and cancer-associated thrombosis, and elevated NETosis in diabetes and its negative impact on wound healing, and will propose a link between PAD4/NETs and age-related organ fibrosis. We identify unresolved issues and new research directions.-Wong, S. L., Wagner, D. D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging.

Formation of Neutrophil Extracellular Traps against Infection and During Inflammation: Boon or a Bane?

Neutrophils are the first line of innate immune defence against pathogens. They have three different processes for directly attacking microorganisms, including phagocytosis, degranulation, and forming neutrophil extracellular traps (NETs). The methods of degranulation and phagocytosis are well established. However, several recent studies have been conducted to understand the potential role of NETs in diseases. The involvement of NETs was shown in several conditions including infections and inflammation. This review will discuss the morphology and mechanisms of NET formation, as well as NET formation against infection and during inflammation.

Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 α

AbstractNeutrophils are highly specialized innate immune effector cells that evolved for antimicrobial host defense. In response to inflammatory stimuli and pathogens, they form neutrophil extracellular traps (NETs), which capture and kill extracellular microbes. Deficient NET formation predisposes humans to severe infection, but, paradoxically, dysregulated NET formation contributes to inflammatory vascular injury and tissue damage. The molecular pathways and signaling mechanisms that control NET formation remain largely uncharacterized. Using primary human neutrophils and genetically manipulated myeloid leukocytes differentiated to surrogate neutrophils, we found that mammalian target of rapamycin (mTOR) regulates NET formation by posttranscriptional control of expression of hypoxia-inducible factor 1 α (HIF-1α), a critical modulator of antimicrobial defenses. Next-generation RNA sequencing, assays of mRNA and protein expression, and analysis of NET deployment by live cell imaging and quantitative histone release showed that mTOR controls NET formation and translation of HIF-1α mRNA in response to lipopolysaccharide. Pharmacologic and genetic knockdown of HIF-1α expression and activity inhibited NET deployment, and inhibition of mTOR and HIF-1α inhibited NET-mediated extracellular bacterial killing. Our studies define a pathway to NET formation involving 2 master regulators of immune cell function and identify potential points of molecular intervention in strategies to modify NETs in disease.