scholarly journals Gut-derived Lipopolysaccharide Promotes Alcoholic Hepatosteatosis and Subsequent Hepatocellular Carcinoma by Stimulating Neutrophil Extracellular Traps Through TLR4

2021 ◽  
Author(s):  
Yang Liu ◽  
Xin Zhang ◽  
Shuo Chen ◽  
Jiazhong Wang ◽  
Shuo Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Intestinal Bacteria ◽  
Neutrophil Infiltration ◽  
Neutrophil Extracellular Traps ◽  
Chronic Alcohol ◽  
Inflammation Markers ◽  
Bacterial Product ◽  
Extracellular Traps ◽  
Stimulation Of

Abstract BackgroundBinge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and which increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and activation of neutrophil extracellular traps (NETs). MethodsSerum from both binge drinking and alcohol-avoiding patients was analyzed. Mouse models of chronical plus binge alcohol indued steatosis and HCC models were used. ResultsA marker of NETs formation, lipopolysaccharide, was significantly higher in alcoholic steatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE KO mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and genesis of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product lipopolysaccharide (LPS). When mice lacking TLR4 received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated. ConclusionFormation of NETs following LPS stimulation of TLR4 upon chronic alcohol usage leads to increased alcoholic steatosis and subsequent HCC.

scholarly journals Histones of Neutrophil Extracellular Traps (NETs) Activate Brain Pericyte via Dectin-1 in Traumatic Brain Injury

2021 ◽  
Author(s):  
Yang-Wuyue Liu ◽  
Jingyu Zhang ◽  
Wanda Bi ◽  
Mi Zhou ◽  
Jiabo Li ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Molecular Mechanisms ◽  
Promoter Sequence ◽  
Neutrophil Infiltration ◽  
Neutrophil Extracellular Traps ◽  
Immunohistochemical Method ◽  
Dependent Manner ◽  
Extracellular Traps ◽  
Factor C

Abstract BackgroundBlood-brain barrier (BBB) disruption and leukocyte infiltration are two pathological features post traumatic brain injury (TBI). However, the role of circulating leukocytes in BBB disruption and the crosstalk between them are not fully elucidated. Neutrophil is the most abundant circulating cell type that migrates into brain tissue when TBI occurs instantly, while brain pericyte occupies a strategic position between circulating cell and interstitial space in BBB. Understanding their interactions is essential to provide insight into the intrinsic relationship and identify biological targets for TBI treatments. MethodsBy analyzing brain tissues from TBI patients and mouse TBI model through immunohistochemical method and flow cytometry, we build the relationship between neutrophils, neutrophil extracellular traps (NETs) and brain pericyte. The components of NETs-related medium were investigated by proteomics and metabolomics to decipher the factors directly regulating pericytes. The molecular mechanisms were deeply explored by WB/CHIP/RT-PCR in primary brain pericyte/pericyte cell line MBVP treated with NETs-formed medium or specific NETs components. In mice TBI model, we also explored the possible therapeutic approaches for TBI treatment that targeting at the axis of neutrophil-NETs-pericyte. ResultsNETs formation is highly enhanced post TBI, inducing the appearance of CD11b expressing brain pericyte simultaneously. This novel CD11b+ pericyte subset is characterized with increased permeability and pro-inflammatory profiles. Mechanistically, recognition of histones from NETs by Dectin-1 on pericyte contributes to CD11b induction in protein kinase C (PKC)-c-Jun-dependent manner. Transcription factor c-Jun directly binds to the promoter sequence of CD11b to enhance its expression in pericyte, conferring pericyte activation, BBB disruption and aggravated neutrophil infiltration post TBI. Either inhibiting NETs formation by Cl-Amidine or blocking Dectin-1 by Laminarin are both beneficial for decreasing neutrophil infiltration and brain pericyte activation post TBI. ConclusionsThese results unfold that “neutrophil-NETs-pericyte” and “histones-Dectin-1-CD11b” are possible cellular and molecular mechanisms for building connection between BBB damage and neutrophil infiltration. Targeting at NETs formation and Dectin-1 are promising treatments for improving neurological outcomes of TBI patients.

scholarly journals Coronavirus disease 2019 (COVID-19): NETosis-associated mechanisms of progression and prospects for therapy regulating the formation of neutrophil extracellular traps (NETs)

2021 ◽  
Vol 6 (4) ◽  
pp. 64-73
Author(s):  
K. A. Aitbaev ◽  
I. T. Murkamilov ◽  
V. V. Fomin ◽  
I. O. Kudaibergenova ◽  
F. A. Yusupov
Keyword(s):  
Molecular Mechanisms ◽  
Adverse Reactions ◽  
Thrombus Formation ◽  
The Elderly ◽  
Neutrophil Extracellular Traps ◽  
The Body ◽  
Surrounding Tissue ◽  
Chronic Respiratory Diseases ◽  
Small Vessels ◽  
Extracellular Traps

Infectious disease COVID-19 caused by the SARS-CoV-2 coronavirus is characterized by high contagiousness, complexity of pathogenesis and unpredictability of the clinical course. In severe cases, which are especially susceptible to men, the elderly and people with underlying medical conditions such as obesity, diabetes, hypertension, cardiovascular and chronic respiratory diseases, the infection leads to respiratory failure and death due to the development of an extensive inflammatory reaction. As a result of many studies, it has been established that one of the leading causes of the severe course and death of patients with COVID-19 is the development of coagulopathy, that is, increased thrombus formation in small vessels due to excessive activity of neutrophils, which form the so-called neutrophil extracellular traps (NETs). Although NETs play a useful role in protecting their host from pathogens, their overgrowth can trigger a cascade of adverse reactions including: the production of antibodies against the host’s DNA (autoimmunization); damage to surrounding tissue; or the occurrence of thromboembolic complications. Therefore, extracellular neutrophil traps and their markers have been identified as targets for new therapeutic strategies aimed at reducing the severity of COVID-19 disease and/or mortality. This article describes the structure of NETs, as well as analyzes the molecular mechanisms that contribute to their overgeneration. In addition, the prospects for COVID-19 therapy aimed at regulating the formation of extracellular traps by creating drugs both limiting the production of NET structures and dissolving their excess amounts in the body of patients are discussed.

scholarly journals Mechanisms and Managements of Influenza and its Related Pneumonia

2021 ◽  
Vol 9 (7) ◽  
Author(s):  
Masafumi Seki
Keyword(s):  
Influenza Virus ◽  
Elderly People ◽  
Bacterial Pneumonia ◽  
Molecular Mechanisms ◽  
Neutrophil Extracellular Traps ◽  
Pneumococcal Vaccines ◽  
Extracellular Traps ◽  
Severe Influenza ◽  
Influenza Pneumonia

Influenza have been a huge issue mainly in elderly people, particularly on the management of patients with pneumonia. The influenza-related pneumonia were generally divided in to two categories, such as primary influenza pneumonia and influenza-related bacterial pneumonia, respectively. The molecular mechanisms, including neutrophil extracellular traps (NETs) might be contributed to severe influenza mediated through the ‘cytokine storms’, similar to COVID-19. Co-infection with influenza virus and bacteria were suggested to synergic, and also exacerbate the influenza. The importance of administration of anti- influenza, including Baloxavir, a novel anti-influenza agent, and preventive efforts centered on vaccinations combined with influenza and pneumococcal vaccines should be considered.

scholarly journals Neutrophil extracellular traps in patients with liver cirrhosis and hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Robin Zenlander ◽  
Sebastian Havervall ◽  
Maria Magnusson ◽  
Jennie Engstrand ◽  
Anna Ågren ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Plasma Levels ◽  
Thrombus Formation ◽  
Laboratory Data ◽  
Neutrophil Extracellular Traps ◽  
Clinical Parameters ◽  
Healthy Controls ◽  
Coagulation Activity ◽  
Extracellular Traps

AbstractNeutrophil extracellular traps (NETs) are web-like structures consisting of DNA, histones and granule proteins, released from neutrophils in thrombus formation, inflammation, and cancer. We asked if plasma levels of the NET markers myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit)-DNA, are elevated in liver cirrhosis and hepatocellular carcinoma (HCC) and if the levels correlate with clinical parameters. MPO-DNA, H3Cit-DNA, and thrombin–antithrombin (TAT) complex, as a marker of coagulation activity, were measured using ELISA in plasma from 82 patients with HCC, 95 patients with cirrhosis and 50 healthy controls. Correlations were made to clinical parameters and laboratory data and patients were followed for a median of 22.5 months regarding thrombosis development. H3Cit-DNA was significantly (p < 0.01) elevated in plasma from cirrhosis (66.4 ng/mL) and HCC (63.8 ng/mL) patients compared to healthy controls (31.8 ng/mL). TAT levels showed similar pattern (3.1, 3.7, and 0.0 µg/mL respectively, p < 0.01). MPO-DNA was significantly (p < 0.01) elevated in cirrhosis patients (0.53 O.D.) as compared to controls (0.33 O.D.). Levels of MPO-DNA and H3Cit-DNA correlated positively with Child–Pugh and MELD score. TAT was increased in all Child–Pugh and MELD groups. In multivariable logistic regression, Child B and C liver cirrhosis were independent predictors of elevated H3Cit-DNA in plasma. Levels of MPO-DNA and H3Cit-DNA were similar in patients with or without history of thrombosis, or thrombus formation during follow-up. In conclusion, plasma markers of NET formation are elevated in liver cirrhosis and correlate to the degree of liver dysfunction in patients with liver cirrhosis and/or HCC. The presence of HCC did not further increase the plasma levels of NET markers as compared to patients with cirrhosis only.

scholarly journals Characterization of Bovine Neutrophil Extracellular Traps Induced by Histamine

2020 ◽  
Author(s):  
Ershun Zhou ◽  
Zhikai Wu ◽  
Xingyi Zhu ◽  
Peixuan Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Nadph Oxidase ◽  
Molecular Mechanisms ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Allergic Diseases ◽  
Neutrophil Extracellular Traps ◽  
Cell Counting ◽  
Dependent Manner ◽  
Extracellular Traps ◽  
Main Components

Abstract BackgroundHistamine plays an central role in many allergic diseases including allergic asthma and allergic rhinitis, and is also involved in bovine laminitis through regulating immune responses. Neutrophil extracellular traps (NETs) formation is a novel effector mechanism of neutrophils to defend against various stimuli. In the present study, we aimed to investigate the role of histamine on bovine NET formation and examined its fundamental molecular mechanisms. ResultsFirstly, the effects of histamine on neutrophil viability was measured by Cell Counting Kit-8 (CCK-8) and Lactate dehydrogenase (LDH) assays. The results showed that histamine had no significant influence on neutrophil viability. Then we characterized histamine-triggered NET formation by confocal microscopy and PicoGreen-derived NETs quantification. Confocal microscopy analyses illustrated NET structures by co-localizing the main components of NETs, and NET quantification revealed that histamine-triggered NETs were released in a dose-dependent manner. In addition, we found reactive oxygen species (ROS) production, phosphorylated extracellular signal-regulated kinase (ERK) and p38 proteins were significantly elevated in histamine-challenged neutrophils. By applying functional inhibitors of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), ERK and p38, histamine-triggered NETs were markedly reduced, indicating their importance in histamine-triggered NET formation. ConclusionsOur findings described histamine-triggered NET formation, and revealed its potential molecular mechanisms via NADPH oxidase, ERK and p38 pathways. This is the first study to depict NET formation induced by histamine, which could provide a new insight into histamine-related diseases.

scholarly journals Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis

Hepatology ◽  
2018 ◽  
Vol 68 (4) ◽  
pp. 1347-1360 ◽  
Author(s):  
Dirk J. van der Windt ◽  
Vikas Sud ◽  
Hongji Zhang ◽  
Patrick R. Varley ◽  
Julie Goswami ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nonalcoholic Steatohepatitis ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps

scholarly journals Role of Neutrophils on the Ocular Surface

2021 ◽  
Vol 22 (19) ◽  
pp. 10386
Author(s):  
Yongseok Mun ◽  
Jin Sun Hwang ◽  
Young Joo Shin
Keyword(s):  
Ocular Surface ◽  
Innate Immune System ◽  
Neutrophil Infiltration ◽  
Neutrophil Extracellular Traps ◽  
Therapeutic Agents ◽  
Innate Immune ◽  
Neutrophil Extracellular Trap ◽  
Extracellular Traps ◽  
Ocular Surface Diseases

The ocular surface is a gateway that contacts the outside and receives stimulation from the outside. The corneal innate immune system is composed of many types of cells, including epithelial cells, fibroblasts, natural killer cells, macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, mucin, and lysozyme. Neutrophil infiltration and degranulation occur on the ocular surface. Degranulation, neutrophil extracellular traps formation, called NETosis, and autophagy in neutrophils are involved in the pathogenesis of ocular surface diseases. It is necessary to understand the role of neutrophils on the ocular surface. Furthermore, there is a need for research on therapeutic agents targeting neutrophils and neutrophil extracellular trap formation for ocular surface diseases.

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