A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics

Mutua, Victoria; Gershwin, Laurel J.

doi:10.1007/s12016-020-08804-7

Cited by 303 publications

(293 citation statements)

References 272 publications

(326 reference statements)

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“…In addition to the progress in knowledge about the specialized immunoprotective functions of NETs, recent research in animal models and in-vitro experiments is providing increasing evidence for the central pathophysiological role of NETs in disease. There is a remarkable spectrum of cardiovascular, inflammatory, autoimmune and metabolic diseases, infectious diseases, and certain septic conditions in which NETs seem to contribute to morbidity and mortality [ 34 ].…”

Section: Net-associated Diseasesmentioning

confidence: 99%

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease

Klopf

Brostjan

Eilenberg

et al. 2021

IJMS

139

112

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Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient’s immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.

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Section: Net-associated Diseasesmentioning

confidence: 99%

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease

Klopf

Brostjan

Eilenberg

et al. 2021

IJMS

139

112

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“…Anti-thrombosis: Heparin is a naturally occurring glycosaminoglycan which is used as an anticoagulant (blood thinner) in the treatment of stable angina, heart attacks and it also antagonizes the effects of histones [ 194 , 195 , 196 ]. Role of Heparin in reduction/inhibition of NETs is enlisted in Table 3 .…”

Section: Vicious Cycle Of the Nets In Copd Inflammationmentioning

confidence: 99%

“…Nucleases: DNAses acts on DNA Matrixes and cleave it and reduces the infiltration of neutrophils hence playing role in inhibition/reduction of NETs ( Table 3 ) [ 196 , 197 ].…”

Section: Vicious Cycle Of the Nets In Copd Inflammationmentioning

confidence: 99%

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Orchestration of Neutrophil Extracellular Traps (Nets), a Unique Innate Immune Function during Chronic Obstructive Pulmonary Disease (COPD) Development

et al. 2021

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Morbidity, mortality and economic burden caused by chronic obstructive pulmonary disease (COPD) is a significant global concern. Surprisingly, COPD is already the third leading cause of death worldwide, something that WHO had not predicted to occur until 2030. It is characterized by persistent respiratory symptoms and airway limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles of gases. Neutrophil is one of the key infiltrated innate immune cells in the lung during the pathogenesis of COPD. Neutrophils during pathogenic attack or injury decide to undergo for a suicidal death by releasing decondensed chromatin entangled with antimicrobial peptides to trap and ensnare pathogens. Casting neutrophil extracellular traps (NETs) has been widely demonstrated to be an effective mechanism against invading microorganisms thus controlling overwhelming infections. However, aberrant and massive NETs formation has been reported in several pulmonary diseases, including chronic obstructive pulmonary disease. Moreover, NETs can directly induce epithelial and endothelial cell death resulting in impairing pulmonary function and accelerating the progression of the disease. Therefore, understanding the regulatory mechanism of NET formation is the need of the hour in order to use NETs for beneficial purpose and controlling their involvement in disease exacerbation. For example, DNA neutralization of NET proteins using protease inhibitors and disintegration with recombinant human DNase would be helpful in controlling excess NETs. Targeting CXC chemokine receptor 2 (CXCR2) would also reduce neutrophilic inflammation, mucus production and neutrophil-proteinase mediated tissue destruction in lung. In this review, we discuss the interplay of NETs in the development and pathophysiology of COPD and how these NETs associated therapies could be leveraged to disrupt NETopathic inflammation as observed in COPD, for better management of the disease.

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“…Apart from increased NET degradation, it is possible to inhibit their formation. Certain inhibitors which block peptidyl arginine deiminase (PAD), an enzyme crucial to NET formation, act as inhibitors of NETosis because they block citrullination, a vital step in NET formation [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular DNA Correlates with Intestinal Inflammation in Chemically Induced Colitis in Mice

Marônek

Gromová

Lipták

et al. 2021

Cells

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Circulating extracellular DNA (ecDNA) is known to worsen the outcome of many diseases. ecDNA released from neutrophils during infection or inflammation is present in the form of neutrophil extracellular traps (NETs). It has been shown that higher ecDNA concentration occurs in a number of inflammatory diseases including inflammatory bowel disease (IBD). Enzymes such as peptidyl arginine deiminases (PADs) are crucial for NET formation. We sought to describe the dynamics of ecDNA concentrations and fragmentation, along with NETosis during a mouse model of chemically induced colitis. Plasma ecDNA concentration was highest on day seven of dextran sulfate sodium (DSS) intake and the increase was time-dependent. This increase correlated with the percentage of cells undergoing NETosis and other markers of disease activity. Relative proportion of nuclear ecDNA increased towards more severe colitis; however, absolute amount decreased. In colon explant medium, the highest concentration of ecDNA was on day three of DSS consumption. Early administration of PAD4 inhibitors did not alleviate disease activity, but lowered the ecDNA concentration. These results uncover the biological characteristics of ecDNA in IBD and support the role of ecDNA in intestinal inflammation. The therapeutic intervention aimed at NETs and/or nuclear ecDNA has yet to be fully investigated.

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A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics

Cited by 303 publications

References 272 publications

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease

Orchestration of Neutrophil Extracellular Traps (Nets), a Unique Innate Immune Function during Chronic Obstructive Pulmonary Disease (COPD) Development

Extracellular DNA Correlates with Intestinal Inflammation in Chemically Induced Colitis in Mice

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