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 Glucagon-Like Peptide-2 Reduces Intestinal Permeability But Does Not Modify the Onset of Type 1 Diabetes in the Nonobese Diabetic Mouse

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 592-599 ◽  
Author(s):  
Irene Hadjiyanni ◽  
Kunmin Karen Li ◽  
Daniel J. Drucker
Keyword(s):  
Type 1 Diabetes ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Gut Barrier ◽  
Nonobese Diabetic ◽  
Gut Barrier Function ◽  
Glucagon Like Peptide

The development of type 1 diabetes (T1D) has been linked to environmental factors and dietary components. Increasing evidence indicates that the integrity of the gut mucosa plays a role in the development of autoimmune diseases, and evidence from both preclinical and clinical studies demonstrates that increased leakiness of the intestinal epithelium precedes the development of type 1 diabetes. However, there is limited information on modulation of gut barrier function and its relationship to diabetes development. Here we show that the nonobese diabetic (NOD) mouse, a model of T1D, exhibits enhanced intestinal transcellular permeability before the development of autoimmune diabetes. Treatment of NOD mice with a glucagon-like peptide 2 (GLP-2) analog, synthetic human [Gly2] glucagon-like peptide-2 (h[Gly2]GLP-2, increased the length and weight of the small bowel and significantly improved jejunal transepithelial resistance. However, chronic administration of once daily h[Gly2]GLP-2 failed to delay or reverse the onset of T1D when treatment was initiated in young, normoglycemic female NOD mice. Furthermore, h[Gly2]GLP-2 administration had no significant effect on lymphocyte subpopulations in NOD mice. These findings demonstrate that h[Gly2]GLP-2-mediated enhancement of gut barrier function in normoglycemic NOD mice disease is not sufficient to prevent or delay the development of experimental T1D. Increased intestinal permeability often precedes the clinical appearance of autoimmune disorders such as celiac disease or type 1 diabetes. These studies show that glucagon-like peptide 2 reduces gut permeability, but not the onset of diabetes in NOD mice.

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 Clinical Analysis of Gut Barrier Dysfunction in Patients with Advanced Colorectal Cancer Undergoing Cytoreductive Surgery and HIPEC

2021 ◽  
Author(s):  
Le lai Ping ◽  
Jiang xu Mian ◽  
Chen Wei
Keyword(s):  
Colorectal Cancer ◽  
Cytoreductive Surgery ◽  
Barrier Function ◽  
Intraperitoneal Injection ◽  
Advanced Colorectal Cancer ◽  
Patient Characteristics ◽  
Barrier Dysfunction ◽  
Large Area ◽  
Gut Barrier ◽  
Gut Barrier Function

Abstract Introduction: Hyperthermic intraperitoneal chemotherapy combinedwith cytoreductive surgery is a preferred treatment option for advanced colorectal cancer patients. However, little is known whether the HIPEC can cause the damage of gut barrier function.Methods: A total of 123 patients underwent surgical resection for advanced CRC. Sixty-five patients were treated HIPEC after cytoreductive surgery whereas 58 patients underwent surgery only. Gut barrier function were evaluated using the expression of serum DAO/D-la/ET on D1/D5/D10 after surgery. Both groups were compared for patient characteristics, perioperative data and gut barrier function. Moreover, rats received intraperitoneal injection of retetrexed to observe possible changes of colonic structure under optical microscope.Results: Both groups were comparable with respect to general patient characteristics and post-operative complications. The HIPEC+CRS group was associated with a higher postoperative serum level of DAO/D-la on D1/D5 (p < 0.05) and ET on D5 after surgery (p < 0.05) than that of the surgery only group. Ten days after surgery showed no statistical difference between the 2 groups (p > 0.05).A large area structure disorder, epithelial necrosis, glandular deformation and a large number of lymphocytes infiltration was found in the lamina propria in animals received intraperitoneal injection of retetrexed.Conclusion: In this study, CRS combined with HIPEC does have but only an irreversible impact on gut barrier for advanced CRC patients.

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.

Increased formation of neutrophil extracellular traps is associated with gut leakage in patients with type 1 but not type 2 diabetes

2019 ◽  
Vol 11 (8) ◽  
pp. 665-673 ◽  
Author(s):  
Qi You ◽  
Dong Mei He ◽  
Guo Fang Shu ◽  
Bo Cao ◽  
Yong Quan Xia ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Gut Leakage

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 Role of Gut Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Xin Dai ◽  
Bangmao Wang
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Barrier Function ◽  
Fatty Liver Disease ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Nonalcoholic Fatty Liver ◽  
Gut Barrier Function

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, and its incidence is increasing year by year. Many efforts have been made to investigate the pathogenesis of this disease. Since 1998 when Marshall proposed the conception of “gut-liver axis,” more and more researchers have paid close attention to the role of gut barrier function in the pathogenesis of NAFLD. The four aspects of gut barrier function, including physical, chemical, biological, and immunological barriers, are interrelated closely and related to NAFLD. In this paper, we present a summary of research findings on the relationship between gut barrier dysfunction and the development of NAFLD, aiming at illustrating the role of gut barrier function in the pathogenesis of this disease.

scholarly journals Genetically obese mice do not show increased gut permeability or faecal bile acid hydrophobicity

2013 ◽  
Vol 110 (6) ◽  
pp. 1157-1164 ◽  
Author(s):  
Lotta K. Stenman ◽  
Reetta Holma ◽  
Helena Gylling ◽  
Riitta Korpela
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Intestinal Permeability ◽  
Low Grade ◽  
Obese Mice ◽  
Gut Permeability ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Genetic Obesity ◽  
Gut Barrier Function

Gut barrier dysfunction may lead to metabolic endotoxaemia and low-grade inflammation. Recent publications have demonstrated gut barrier dysfunction in obesity induced by a diet high in fat, and a pathogenetic role for luminal bile acids has been proposed. We aimed to investigate whether genetically obese mice develop increased gut permeability and alterations in luminal bile acids on a diet with a regular fat content. We used seven obese male ob/ob mice of C57BL/6J background and ten male wild-type (WT) mice of the same strain. Faeces were collected for bile acid analysis. Intestinal permeability was measured in an Ussing chamber upon euthanasia, using 4 kDa fluorescein isothiocyanate dextran, as per mille (‰, 1/1000) of translocated dextran. We analysed the liver expression of lipopolysaccharide-binding protein (LBP), as well as serum LBP (ELISA). Intestinal permeability was not affected by genetic obesity (jejunum: 0·234 (sem 0·04) ‰ for obese v. 0·225 (sem 0·03) ‰ for WT, P= 0·93; colon: 0·222 (sem 0·06) ‰ for obese v. 0·184 (sem 0·03) ‰ for WT, P= 0·86), nor was liver LBP expression (relative expression: 0·55 (sem 0·08) for obese v. 0·55 (sem 0·13) for WT, P= 0·70). Serum LBP was 2·5-fold higher in obese than in WT mice (P= 0·001). Obese mice had increased daily excretion of total bile acids, but their faecal bile acid hydrophobicity was unchanged. In conclusion, genetic obesity did not impair gut barrier function in mice on a regular chow diet, nor was faecal bile acid hydrophobicity affected.

The gut: central organ in nutrient requirements and metabolism

1994 ◽  
Vol 72 (3) ◽  
pp. 260-265 ◽  
Author(s):  
Michael L. McBurney
Keyword(s):  
Metabolic Response ◽  
Short Chain Fatty Acids ◽  
The Body ◽  
Whole Body ◽  
Nutrient Requirements ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Accidental Injury ◽  
Gut Barrier Function ◽  
Whole Body Metabolism

The gut is an important organ, which not only digests and absorbs food but selectively excludes bacteria and toxins from entering the body. It has one of the highest rates of protein turnover of any tissue in the body. Maintenance of epithelial cell proliferation and secretory, digestive, and gut-associated lymphatic tissues (GALT) function requires a constant supply of substrates. A primary feature of the metabolic response to fasting, accidental injury, or surgery is accelerated skeletal muscle proteolysis and translocation of amino acids from the periphery to visceral organs. Nevertheless, the serosal supply of nutrients may be inadequate to maintain normal gut barrier function. The following factors influencing gut nutrient requirements and the effect of the gut on the whole-body metabolism are discussed: (i) diet composition and gut mass, (ii) physiological and pathologic nutrient requirements of epithelial and GALT cells, (iii) route of nutrition (enteral versus parenteral), and (iv) nutrient inadequancy and gut barrier dysfunction (structural or immune mediated).Key words: gastrointestine, metabolism, gut-associated lymph tissue, glutamine, short-chain fatty acids.

scholarly journals Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Shilong Sun ◽  
Zehua Duan ◽  
Xinyu Wang ◽  
Chengnan Chu ◽  
Chao Yang ◽  
...  
Keyword(s):  
Er Stress ◽  
Intestinal Epithelial Cell ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Neutrophil Extracellular Traps ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Extracellular Traps ◽  
Epithelial Cell Death ◽  
Stress Activation

AbstractIncreased neutrophil extracellular traps (NETs) formation has been found to be associated with intestinal inflammation, and it has been reported that NETs may drive the progression of gut dysregulation in sepsis. However, the biological function and regulation of NETs in sepsis-induced intestinal barrier dysfunction are not yet fully understood. First, we found that both circulating biomarkers of NETs and local NETs infiltration in the intestine were significantly increased and had positive correlations with markers of enterocyte injury in abdominal sepsis patients. Moreover, the levels of local citrullinated histone 3 (Cit H3) expression were associated with the levels of BIP expression. To further confirm the role of NETs in sepsis-induced intestinal injury, we compared peptidylarginine deiminase 4 (PAD4)-deficient mice and wild-type (WT) mice in a lethal septic shock model. In WT mice, the Cit H3-DNA complex was markedly increased, and elevated intestinal inflammation and endoplasmic reticulum (ER) stress activation were also found. Furthermore, PAD4 deficiency alleviated intestinal barrier disruption and decreased ER stress activation. Notably, NETs treatment induced intestinal epithelial monolayer barrier disruption and ER stress activation in a dose-dependent manner in vitro, and ER stress inhibition markedly attenuated intestinal apoptosis and tight junction injury. Finally, TLR9 antagonist administration significantly abrogated NETs-induced intestinal epithelial cell death through ER stress inhibition. Our results indicated that NETs could contribute to sepsis-induced intestinal barrier dysfunction by promoting inflammation and apoptosis. Suppression of the TLR9–ER stress signaling pathway can ameliorate NETs-induced intestinal epithelial cell death.

Sign in / Sign up

Export Citation Format

Share Document