scholarly journals Neutrophil Extracellular Traps Induce Intestinal Damage and Thrombotic Tendency in Inflammatory Bowel Disease

2019 ◽  
Vol 14 (2) ◽  
pp. 240-253 ◽  
Author(s):  
Tao Li ◽  
Chunxu Wang ◽  
Yingmiao Liu ◽  
Baorong Li ◽  
Wujian Zhang ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Neutrophil Extracellular Traps ◽  
Central Component ◽  
Intestinal Damage ◽  
Colon Tissue ◽  
Extracellular Traps ◽  
Dnase Treatment ◽  
Inflammatory Bowel ◽  
Thrombotic Tendency

Abstract Background and Aims Despite the presence of neutrophil extracellular traps [NETs] in inflamed colon having been confirmed, the role of NETs, especially the circulating NETs, in the progression and thrombotic tendency of inflammatory bowel disease [IBD] remains elusive. We extended our previous study to prove that NETs constitute a central component in the progression and prothrombotic state of IBD. Methods In all 48 consecutive patients with IBD were studied. Acute colitis was induced by the treatment of C57BL/6 mice with 3.5% dextran sulphate sodium [DSS] in drinking water for 6 days. Peripheral blood neutrophils and sera were collected from IBD patients and murine colitis models. Exposed phosphatidylserine [PS] was analysed with flow cytometry and confocal microscopy. Procoagulant activity was evaluated using clotting time, purified coagulation complex, and fibrin formation assays. Results We observed higher plasma NET levels and presence of NETs in colon tissue in patients with active IBD. More importantly, NETs were induced in mice with DSS colitis, and inhibition of NET release attenuated colitis as well as colitis-associated tumorigenesis. NET degradation through DNase administration decreased cytokine levels during DSS-induced colitis. In addition, DNase treatment also significantly attenuated the accelerated thrombus formation and platelet activation observed in DSS-induced colitis. NETs triggered PS-positive microparticle release and PS exposure on platelets and endothelial cells partially through TLR2 and TLR4, converting them to a procoagulant phenotype. Conclusions NETs exacerbate colon tissue damage and drive thrombotic tendency during active IBD. Strategies directed against NET formation may offer a potential therapeutic approach for the treatment of IBD.

scholarly journals Neutrophil Extracellular Traps Exacerbate Inflammatory Responses and Thrombotic Tendency in Both a Murine Colitis Model and Patients with Inflammatory Bowel Disease

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 994-994
Author(s):  
Muhua Cao ◽  
Muxin Yu ◽  
Yan Zhang ◽  
Dongxia Tong ◽  
Li Guo ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Inflammatory Responses ◽  
Neutrophil Extracellular Traps ◽  
Dnase I ◽  
Dna Complexes ◽  
Extracellular Traps ◽  
Inflammatory Bowel ◽  
Net Release ◽  
Thrombotic Tendency

Abstract Introduction: Inflammatory bowel disease (IBD) arises from a combination of genetic susceptibility and environmental factors, which trigger inappropriate mucosal inflammatory responses, the pathogenesis of which still remains exclusive. Therapeutic strategies for IBD mainly focus on controlling the active inflammation, intestinal epithelial barrier destruction and thrombotic tendency. Our group has recently demonstrated, for the first time, that patients with active IBD exhibited enhanced neutrophil extracellular traps (NETs) release, leading to a hypercoagulable state (He Z et al, Thromb Haemost 2016). However, the mechanisms by which NETs drive the pathogenesis of IBD remain unclear. The aim of this study was to further identify the novel role of NETs in the initiation and progression of IBD. Methods: 51 consecutive patients with IBD were studied. Disease activity was assessed by using the Mayo Score (MS) for patients with (ulcerative colitis) UC and (Crohn's disease) CD. Acute disease was induced by the treatment of C57BL/6 mice with 3.5% DSS in drinking water for 6 days. For an inhibition assay, DNase I perfusion or neutrophil depletion with anti-Ly6G antibody (1A8 clone) was performed. Cell-free DNA (cf-DNA) was quantified using the Quant-iT PicoGreen dsDNA Assay Kit. ELISA was used to detect MPO-DNA complexes, TAT (thrombin-antithrombin) complexes, nucleosomes, chemokines, and cytokines. Results: Compared to subjects with inactive UC or CD, patients with active UC or CD had significantly increased levels of cf-DNA, nucleosomes and NETs formation (MPO-DNA complexes). Neutrophils from active CD and UC demonstrated more spontaneous NET release as compared to inactive patients and controls. In DSS-induced colitis, significantly higher levels of serum cf-DNA and NETs formation were found in mice on day 4 and day 6 after DSS initiation. Western blot analysis and immunofluorescent staining of colonic tissues from mice with DSS-induced colitis showed increased NETs release and deposition. Mice treated with DNase I were protected from DSS-induced colitis, showing slighter weight loss, lower disease activity index, improved survival rate, diminished colon length shortening and decreased histologic signs of inflammation compared with controls. Furthermore, DNase I perfusion also decreased MPO levels by 62% on day 4 and by 58% on day 6, indicating DNase down-regulated neutrophil infiltration during DSS-induced colitis. The expression of Interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, CXCL2, CXCL10 and monocyte chemotactic protein-1(MCP-1) messenger RNA in colonic extracts were lower in DNase I perfused DSS-induced mice compared with saline perfused DSS-induced mice. Incubation of normal platelets with NETs from active IBD patients, but not inactive IBD patients, significantly enhanced their procoagulant activity by 32% and the ability to support fibrin formation by 42%. This effect was blocked by DNase I treatment. Conclusions: We have extended our previous study and demonstrated that NETs constitute a central component in the initiation and progression of colitis through mediating inflammation cell infiltration, driving cytokines release and thrombotic tendency. NET degradation through DNase I perfusion protected mice from severe DSS-induced colitis. Thus, strategies focusing on the application of DNase I to accelerate the degradation of excessive NET release and deposition may offer potential therapeutic benefits for patients with inflammatory bowel disease. Disclosure of Interest: None declared. Disclosures No relevant conflicts of interest to declare.

THE ROLE OF MYELOPEROXIDASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 160 (3) ◽  
pp. S5-S6
Author(s):  
Belal Chami ◽  
Gulfam Ahmad ◽  
Angie Schroder ◽  
Patrick San Gabriel ◽  
Paul Witting
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Inflammatory Bowel

Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease

2016 ◽  
Vol 115 (04) ◽  
pp. 738-751 ◽  
Author(s):  
Ruishuang Ma ◽  
Yan Zhang ◽  
Muhua Cao ◽  
Tao Li ◽  
Zhipeng Yao ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Thromboembolic Event ◽  
Neutrophil Extracellular Traps ◽  
Hypercoagulable State ◽  
Coagulation Time ◽  
Extracellular Traps ◽  
Fibrin Formation ◽  
Inflammatory Bowel ◽  
Epidemiological Association

SummaryInflammatory bowel disease (IBD)-associated thromboembolic event often lacks precise aetiology. The aim of this study was to investigate the contribution of phosphatidylserine (PS) exposure and neutrophil extracellular traps (NETs) towards the hypercoagulable state in IBD. We demonstrated that the levels of PS exposed MPs and the sources of MP-origin, platelets, erythrocytes, leukocytes and cultured endothelial cells (ECs) were higher in IBD groups than in healthy controls using flow cytometry and confocal microscopy. Wright-Giemsa and immunofluorescence staining demonstrated that the elevated NETs were released by activated IBD neutrophils or by control neutrophils treated with IBD sera obtained from patients with the active disease. MPs and MP-origin cells in IBD groups, especially in active stage, markedly shortened coagulation time and had increased levels of fibrin, thrombin and FXa production as assessed by coagulation function assays. Importantly, we found that on stimulated ECs, PS rich membranes provided binding sites for FXa and FVa, promoting fibrin formation while TNF blockage or IgG depletion attenuated this effect. Treatment of control neutrophils with TNF and isolated IgG from PR3-ANCA-positive active IBD patients also resulted in the release of NETs. Blockade of PS with lactadherin prolonged coagulation time, decreased fibrin formation to control levels, and inhibited the procoagulant enzymes production in the MPs and MP-origin cells. NET cleavage by DNase I partly decreased PCA in IBD or stimulated neutrophils. Our study reveals a previously unrecognised link between hypercoagulable state and PS exposure or NETs, and may further explain the epidemiological association of thrombosis within IBD patients.

Neutrophil extracellular traps in pediatric inflammatory bowel disease

2018 ◽  
Vol 68 (9) ◽  
pp. 517-523 ◽  
Author(s):  
Yehonatan Gottlieb ◽  
Ronit Elhasid ◽  
Sivan Berger-Achituv ◽  
Eli Brazowski ◽  
Anat Yerushalmy-Feler ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Pediatric Inflammatory Bowel Disease ◽  
Inflammatory Bowel

scholarly journals Cell-Free Nucleic Acids and their Emerging Role in the Pathogenesis and Clinical Management of Inflammatory Bowel Disease

2019 ◽  
Vol 20 (15) ◽  
pp. 3662 ◽  
Author(s):  
Zuzana Kubiritova ◽  
Jan Radvanszky ◽  
Roman Gardlik
Keyword(s):  
Inflammatory Bowel Disease ◽  
Nucleic Acids ◽  
Autoimmune Diseases ◽  
Bowel Disease ◽  
Neutrophil Extracellular Traps ◽  
Inactive Disease ◽  
Potential Therapeutic Target ◽  
Extracellular Traps ◽  
Inflammatory Processes ◽  
Inflammatory Bowel

Cell-free nucleic acids (cfNAs) are defined as any nucleic acids that are present outside the cell. They represent valuable biomarkers in various diagnostic protocols such as prenatal diagnostics, the detection of cancer, and cardiovascular or autoimmune diseases. However, in the current literature, little is known about their implication in inflammatory bowel disease (IBD). IBD is a group of multifactorial, autoimmune, and debilitating diseases with increasing incidence worldwide. Despite extensive research, their etiology and exact pathogenesis is still unclear. Since cfNAs were observed in other autoimmune diseases and appear to be relevant in inflammatory processes, their role in the pathogenesis of IBD has also been suggested. This review provides a summary of knowledge from the available literature about cfDNA and cfRNA and the structures involving them such as exosomes and neutrophil extracellular traps and their association with IBD. Current studies showed the promise of cfNAs in the management of IBD not only as biomarkers distinguishing patients from healthy people and differentiating active from inactive disease state, but also as a potential therapeutic target. However, the detailed biological characteristics of cfNAs need to be fully elucidated in future experimental and clinical studies.

scholarly journals A4 THE CIRCADIAN TIMING OF INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 4-5
Author(s):  
Z Taleb ◽  
K Stokes ◽  
H Wang ◽  
S M Collins ◽  
W I Khan ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Circadian Clock ◽  
Bowel Disease ◽  
Mutant Mice ◽  
Intestinal Epithelial ◽  
Wild Type ◽  
Colon Tissue ◽  
Rhythmic Expression ◽  
Inflammatory Bowel

Abstract Background The circadian clock is a highly conserved molecular pacemaker found in nearly every cell of the body. It consists of the genes BMAL1 and CLOCK that positively regulate CRY and PER, their negative regulators, resulting in a transcription/translation feedback loop that has a 24 hour cycle. This core clock mechanism drives the rhythmic expression of over 40% of the genome in a tissue-specific manner and therefore imposes 24 hour rhythms on many physiological processes. Shift work, which causes disruptions to the natural 24 hour physiological rhythms, has been shown to lead to an increased incidence of inflammatory bowel disease (IBD). Aims This study aims to characterize daily rhythms in inflammation and regeneration of the colon upon induction of acute colitis. We also aim to investigate the intestinal epithelial-specific effects of circadian clock disruption on overall disease progression. We hypothesize that the absence of a functional circadian clock eliminates proliferation rhythms of intestinal epithelial cells and disrupts the rhythms of inflammatory cytokines, thereby increasing the pathogenesis of IBD. Methods We tested the role of the clock in IBD using BMAL1+/+ (wild type) and BMAL1-/- (null mutant) mice. We also investigated the effects of the circadian clock specific to intestinal epithelial tissue using Vil+/+;BMAL1flox/flox (control) and VilCre/+;BMAL1flox/flox (conditional intestinal epithelial mutant) mice. Dextran Sulfate Sodium (DSS) was applied to induce acute colitis. Results We observed significantly decreased survival of BMAL1 circadian clock mutant mice when given colitis. A histology analysis indicates increased lesioning and overall inflammation in BMAL1-/- colon tissue. Disease activity and cytokine analyses reveal time-dependent severity in inflammatory response that is worse in BMAL1-/- mice. To test the circadian rhythms in intestinal regeneration of mice with IBD, we performed a 24 hour analysis comparing epithelial cell proliferation and cell death in colon tissue. We observed rhythmic expression of phosphor-histone H3 (a mitosis marker) in wild type mice which is eliminated in the BMAL1-/- lacking a circadian clock. Cell death which was measured by caspase 3 did not exhibit any differences between genotypes. Based on these results, we conclude that the loss of clock function leads to impaired regeneration during IBD, in part due to decreased and arrhythmic cell proliferation. Preliminary results in our VilCre/+;BMAL1flox/flox conditional intestinal epithelial mutant mice indicate that some of these effects may be epithelial-specific. Conclusions Our results support a critical role of the circadian clock in inflammatory bowel disease development. These data highlight that the circadian clock affects the regenerative abilities of intestinal epithelial cells. Funding Agencies CIHRChron’s and Colitis Canada, Ontario, University of Windsor

scholarly journals The Role of Citrullination in Inflammatory Bowel Disease: A Neglected Player in Triggering Inflammation and Fibrosis?

2020 ◽  
Vol 27 (1) ◽  
pp. 134-144 ◽  
Author(s):  
Gabriele Dragoni ◽  
Gert De Hertogh ◽  
Séverine Vermeire
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Posttranslational Modification ◽  
Disease Process ◽  
Special Focus ◽  
Extracellular Traps ◽  
Fundamental Process ◽  
Gene Expression Analyses ◽  
Inflammatory Bowel

Abstract Citrullination is a posttranslational modification of proteins mediated by a specific family of enzymes called peptidylarginine deiminases (PAD). Dysregulation of these enzymes is involved in the etiology of various diseases, from cancer to autoimmune disorders. In inflammatory bowel disease (IBD), data for a role of citrullination in the disease process are starting to accumulate at different experimental levels including gene expression analyses, RNA, and protein quantifications. Most data have been generated in ulcerative colitis, but data in Crohn disease are lacking so far. In addition, the citrullination of histones is the fundamental process promoting inflammation through the formation of neutrophil extracellular traps (NETs). Interestingly, NETs have also been shown to activate fibroblasts into myofibroblasts in fibrotic interstitial lung disease. Therefore, citrullination merits more thorough study in the bowel to determine its role in driving disease complications such as fibrosis. In this review we describe the process of citrullination and the different players in this pathway, the role of citrullination in autoimmunity with a special focus on IBD, the emerging role for citrullination and NETs in triggering fibrosis, and, finally, how this process could be therapeutically targeted.

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