scholarly journals Histone citrullination: a new target for tumors

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Dongwei Zhu ◽  
Yue Zhang ◽  
Shengjun Wang
Keyword(s):  
Gene Regulation ◽  
Gene Transcription ◽  
Neutrophil Extracellular Traps ◽  
Arginine Deiminase ◽  
Physiological Regulation ◽  
Extracellular Traps ◽  
Main Protein ◽  
Histone Citrullination ◽  
Protein Components ◽  
The Relationship

AbstractAs the main protein components of chromatin, histones play central roles in gene regulation as spools of winding DNA. Histones are subject to various modifications, including phosphorylation, acetylation, glycosylation, methylation, ubiquitination and citrullination, which affect gene transcription. Histone citrullination, a posttranscriptional modification catalyzed by peptidyl arginine deiminase (PAD) enzymes, is involved in human carcinogenesis. In this study, we highlighted the functions of histone citrullination in physiological regulation and tumors. Additionally, because histone citrullination involves forming neutrophil extracellular traps (NETs), the relationship between NETs and tumors was illustrated. Finally, the clinical application of histone citrullination and PAD inhibitors was discussed.

scholarly journals Silver Nanoparticles Induce Neutrophil Extracellular Traps Via Activation of PAD and Neutrophil Elastase

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 317
Author(s):  
HanGoo Kang ◽  
Jinwon Seo ◽  
Eun-Jeong Yang ◽  
In-Hong Choi
Keyword(s):  
Silver Nanoparticles ◽  
Neutrophil Elastase ◽  
Mammalian Cells ◽  
Antimicrobial Properties ◽  
Neutrophil Extracellular Traps ◽  
Arginine Deiminase ◽  
Human Neutrophils ◽  
Extracellular Traps ◽  
Peptidyl Arginine Deiminase ◽  
Key Factor

Silver nanoparticles (AgNPs) are widely used in various fields because of their antimicrobial properties. However, many studies have reported that AgNPs can be harmful to both microorganisms and humans. Reactive oxygen species (ROS) are a key factor of cytotoxicity of AgNPs in mammalian cells and an important factor in the immune reaction of neutrophils. The immune reactions of neutrophils include the expulsion of webs of DNA surrounded by histones and granular proteins. These webs of DNA are termed neutrophil extracellular traps (NETs). NETs allow neutrophils to catch and destroy pathogens in extracellular spaces. In this study, we investigated how AgNPs stimulate neutrophils, specifically focusing on NETs. Freshly isolated human neutrophils were treated with 5 or 100 nm AgNPs. The 5 nm AgNPs induced NET formation, but the 100 nm AgNPs did not. Subsequently, we investigated the mechanism of AgNP-induced NETs using known inhibitors related to NET formation. AgNP-induced NETs were dependent on ROS, peptidyl arginine deiminase, and neutrophil elastase. The result in this study indicates that treatment of 5 nm AgNPs induce NET formation through histone citrullination by peptidyl arginine deiminase and histone cleavage by neutrophil elastase.

scholarly journals The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Yilu Zhou ◽  
Weimin Tao ◽  
Fuyi Shen ◽  
Weijia Du ◽  
Zhendong Xu ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Neutrophil Extracellular Traps ◽  
Vital Role ◽  
Extracellular Traps ◽  
Protein Components ◽  
Cancer Associated Thrombosis ◽  
Coagulation Pathway

Neutrophils play a vital role in the formation of arterial, venous and cancer-related thrombosis. Recent studies have shown that in a process known as NETosis, neutrophils release proteins and enzymes complexed to DNA fibers, collectively called neutrophil extracellular traps (NETs). Although NETs were originally described as a way for the host to capture and kill bacteria, current knowledge indicates that NETs also play an important role in thrombosis. According to recent studies, the destruction of vascular microenvironmental homeostasis and excessive NET formation lead to pathological thrombosis. In vitro experiments have found that NETs provide skeletal support for platelets, red blood cells and procoagulant molecules to promote thrombosis. The protein components contained in NETs activate the endogenous coagulation pathway to promote thrombosis. Therefore, NETs play an important role in the formation of arterial thrombosis, venous thrombosis and cancer-related thrombosis. This review will systematically summarize and explain the study of NETs in thrombosis in animal models and in vivo experiments to provide new targets for thrombosis prevention and treatment.

scholarly journals Nanomaterial Exposure Induced Neutrophil Extracellular Traps: A New Target in Inflammation and Innate Immunity

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Hang Yang ◽  
Tony N. Marion ◽  
Yi Liu ◽  
Lingshu Zhang ◽  
Xue Cao ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Immune Responses ◽  
Myeloid Cell ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Cell Type ◽  
Extracellular Traps ◽  
Pharmaceutical Industries ◽  
The Relationship

Nanotechnology has become a novel subject with impact in many research and technology areas. Nanoparticles (NPs), as a key component in nanotechnology, are widely used in many areas such as optical, magnetic, electrical, and mechanical engineering. The biomedical and pharmaceutical industries have embraced NPs as a viable drug delivery modality. As such, the potential for NP-induced cytotoxicity has emerged as a major concern for NP drug delivery systems. Thus, it is important to understand how NPs affect the innate immune system. As the most abundant myeloid cell type in innate immune responses, neutrophils are critical for concerns about potentially toxic side effects of NPs. When activated by innate immune stimuli, neutrophils may initiate NETosis to release neutrophil extracellular traps (NETs). Herein, we have reviewed the relationship between NPs and the induction of NETosis and release of NETs.

scholarly journals Neutrophil Extracellular Traps Promote the Development of Intracranial Aneurysm Rupture

Hypertension ◽  
2021 ◽  
Author(s):  
Masaaki Korai ◽  
James Purcell ◽  
Yoshinobu Kamio ◽  
Kazuha Mitsui ◽  
Hajime Furukawa ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Interleukin 1 ◽  
Neutrophil Extracellular Traps ◽  
Aneurysm Rupture ◽  
Arginine Deiminase ◽  
Intercellular Adhesion Molecule ◽  
Necrosis Factor Alpha ◽  
Extracellular Traps ◽  
Peptidyl Arginine Deiminase ◽  
Aneurysm Wall

Potential roles for neutrophils in the pathophysiology of intracranial aneurysm have long been suggested by clinical observations. The presence of neutrophil enzymes in the aneurysm wall has been associated with significant increases in rupture risk. However, the mechanisms by which neutrophils may promote aneurysm rupture are not well understood. Neutrophil extracellular traps (NETs) were implicated in many diseases that involve inflammation and tissue remodeling, including atherosclerosis, vasculitis, and abdominal aortic aneurysm. Therefore, we hypothesized that NETs may promote the rupture of intracranial aneurysm, and that removal of NETs can reduce the rate of rupture. We employed both pharmacological and genetic approaches for the disruption of NETs and used a mouse model of intracranial aneurysm to investigate the roles of NETs in the development of intracranial aneurysm rupture. Here, we showed that NETs are detected in human intracranial aneurysms. Both global and granulocyte-specific knockout of peptidyl arginine deiminase 4 (an enzyme essential for NET formation) reduced the rate of aneurysm rupture. Pharmacological blockade of the NET formation by Cl-amidine also reduced the rate of aneurysm rupture. In addition, the resolution of already formed NETs by deoxyribonuclease was effective against aneurysm rupture. Inhibition of NETs formation with Cl-amidine decreased mRNA expression of proinflammatory cytokines (intercellular adhesion molecule 1 (ICAM-1), interleukin 1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α)) in cerebral arteries. These data suggest that NETs promote the rupture of intracranial aneurysm. Pharmacological removal of NETs, by inhibition of peptidyl arginine deiminase 4 or resolution of already-formed NETs, may represent a potential therapeutic strategy for preventing aneurysmal rupture.

Neutrophil extracellular traps mediate joint hyperalgesia induced by immune inflammation

Rheumatology ◽  
2020 ◽  
Author(s):  
Ayda Henriques Schneider ◽  
Caio Cavalcante Machado ◽  
Flávio Protásio Veras ◽  
Alexandre Gomes de Macedo Maganin ◽  
Flávio Falcão Lima de Souza ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Neutrophil Extracellular Traps ◽  
Arginine Deiminase ◽  
Human Neutrophils ◽  
Oedema Formation ◽  
Extracellular Traps ◽  
Mechanical Threshold ◽  
Articular Pain ◽  
Dose Dependent

Abstract Objective To evaluate the role of neutrophil extracellular traps (NETs) in the genesis of joint hyperalgesia using an experimental model of arthritis and transpose the findings to clinical investigation. Methods C57BL/6 mice were subjected to antigen-induced arthritis (AIA) and treated with Pulmozyme (PLZ) to degrade NETs or Cl-amidine to inhibit NET production. Oedema formation, the histopathological score and mechanical hyperalgesia were evaluated. NETs were injected intra-articularly in wild type (WT), Tlr4−/−, Tlr9−/−, Tnfr1−/− and Il1r−/− mice, and the levels of cytokines and Cox2 expression were quantified. NETs were also quantified from human neutrophils isolated from RA patients and individual controls. Results AIA mice had increased NET concentration in joints, accompanied by increased Padi4 gene expression in the joint cells. Treatment of AIA mice with a peptidyl arginine deiminase 4 inhibitor or with PLZ inhibited the joint hyperalgesia. Moreover, the injection of NETs into joints of naïve animals generated a dose-dependent reduction of mechanical threshold, an increase of articular oedema, inflammatory cytokine production and cyclooxygenase-2 expression. In mice deficient for Tnfr1, Il1r, Tlr4 and Tlr9, joint hyperalgesia induced by NETs was prevented. Last, we found that neutrophils from RA patients were more likely to release NETs, and the increase in synovial fluid NET concentration correlated with an increase in joint pain. Conclusion The findings indicate that NETs cause hyperalgesia possibly through Toll-like receptor (TLR)-4 and TLR-9. These data support the idea that NETs contribute to articular pain, and this pathway can be an alternative target for the treatment of pain in RA.

scholarly journals Neutrophil Extracellular Traps Caused by Gut Leakage Trigger the Autoimmune Response in Nonobese Diabetic Mice

2022 ◽  
Vol 12 ◽  
Author(s):  
Qi You ◽  
Yiming Shen ◽  
Yiling Wu ◽  
Yuyan Li ◽  
Chang Liu ◽  
...  
Keyword(s):  
Nod Mice ◽  
Neutrophil Extracellular Traps ◽  
Arginine Deiminase ◽  
Autoimmune Response ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Extracellular Traps ◽  
Nonobese Diabetic ◽  
Gut Barrier Function ◽  
Gut Leakage

Increased formation of neutrophil extracellular traps (NETs) is associated with gut leakage in type 1 diabetes (T1D). To explore the mechanism of how enteropathy exacerbated by NETs triggers pancreatic autoimmunity in T1D, we carried out a correlation analysis for NET formation with gut barrier functions and autoimmunity in nonobese diabetic (NOD) mice. Inducing chronic colitis or knocking out of peptidyl arginine deiminase type 4 (PAD4) in NOD mice were used to further study the effect of NET formation on the progression of T1D. Microbial alterations in Deferribacteres and Proteobacteria, along with the loss of gut barrier function, were found to be associated with increased endotoxin and abnormal formation of NETs in NOD mice. Both DSS-induced colitis and knockout of PAD4 in NOD mice indicated that PAD4-dependent NET formation was involved in the aggravation of gut barrier dysfunction, the production of autoantibodies, and the activation of enteric autoimmune T cells, which then migrated to pancreatic lymph nodes (PLNs) and caused self-damage. The current study thus provides evidence that PAD4-dependent NET formation is engaged in leaky gut triggering pancreatic autoimmunity and suggests that either degradation of NETs or inhibition of NET formation may be helpful for innovative therapeutic interventions in T1D.

scholarly journals Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Soichiro Watanabe ◽  
Yohei Iwata ◽  
Hidehiko Fukushima ◽  
Kenta Saito ◽  
Yoshihito Tanaka ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Severity Index ◽  
Neutrophil Extracellular Traps ◽  
Skin Lesions ◽  
Arginine Deiminase ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Imiquimod Cream ◽  
Extracellular Traps ◽  
Cytokines And Chemokines

AbstractLoss-of-function mutations in the interleukin (IL)-36 gene IL36RN are associated with psoriasis. The importance of neutrophil extracellular traps (NETs), web-like structures composed of neutrophil DNA, in the pathogenesis of psoriasis has been unclear. Here, we aimed to clarify the role of NET signaling in the deficiency of IL36 receptor antagonist (DITRA). We evaluated the severity of psoriasis-like lesions induced by imiquimod cream treatment in Il36rn−/− mice. The mRNA levels of psoriasis-related cytokines were measured via real-time reverse transcription polymerase chain reaction, and the effects of Cl-amidine, a peptidyl arginine deiminase 4 (PAD4) inhibitor, on psoriasis-like lesions were evaluated. PAD4 is a histone-modifying enzyme that is involved in NET formation. Psoriasis area and severity index scores, epidermal thickness, and infiltrated neutrophil counts were significantly increased in Il36rn−/− mice; NET formation was confirmed pathologically. Several cytokines and chemokines were upregulated in the skin lesions of Il36rn−/− mice and Cl-amidine treatment improved these psoriasis-like lesions. These results suggest that NET formation plays an important role in the pathology of psoriasis-like lesions in these mice and might represent a promising therapeutic target for DITRA.

scholarly journals COVID-19 and Neutrophils: The Relationship between Hyperinflammation and Neutrophil Extracellular Traps

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Leandro Borges ◽  
Tania Cristina Pithon-Curi ◽  
Rui Curi ◽  
Elaine Hatanaka
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Function ◽  
Critical Function ◽  
The Past ◽  
Extracellular Traps ◽  
Neutrophil Response ◽  
The Relationship ◽  
Severe Lung

Coronavirus disease 2019 (COVID-19) is a virus-induced respiratory disease that may progress to acute respiratory distress syndrome (ARDS) and is triggered by immunopathological mechanisms that cause excessive inflammation and leukocyte dysfunction. Neutrophils play a critical function in the clearance of bacteria with specific mechanisms to combat viruses. The aim of this review is to highlight the current advances in the pathways of neutrophilic inflammation against viral infection over the past ten years, focusing on the production of neutrophil extracellular traps (NETs) and its impact on severe lung diseases, such as COVID-19. We focused on studies regarding hyperinflammation, cytokine storms, neutrophil function, and viral infections. We discuss how the neutrophil’s role could influence COVID-19 symptoms in the interaction between hyperinflammation (overproduction of NETs and cytokines) and the clearance function of neutrophils to eliminate the viral infection. We also propose a more in-depth investigation into the neutrophil response mechanism targeting NETosis in the different phases of COVID-19.

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