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Venizelos Papayannopoulos - One of the best experts on this subject based on the ideXlab platform.
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Neutrophil Extracellular Traps in immunity and disease
Nature Reviews Immunology, 2018Co-Authors: Venizelos PapayannopoulosAbstract:Neutrophils are innate immune phagocytes that have a central role in immune defence. Our understanding of the role of Neutrophils in pathogen clearance, immune regulation and disease pathology has advanced dramatically in recent years. Web-like chromatin structures known as Neutrophil Extracellular Traps (NETs) have been at the forefront of this renewed interest in Neutrophil biology. The identification of molecules that modulate the release of NETs has helped to refine our view of the role of NETs in immune protection, inflammatory and autoimmune diseases and cancer. Here, I discuss the key findings and concepts that have thus far shaped the field of NET biology.
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Neutrophil Extracellular Traps license macrophages for cytokine production in atherosclerosis
Science, 2015Co-Authors: Annika Warnatsch, Marianna Ioannou, Qian Wang, Venizelos PapayannopoulosAbstract:Secretion of the cytokine interleukin-1β (IL-1β) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1β, and then endogenous “danger” signals activate innate immune signaling complexes called inflammasomes to process IL-1β for secretion. Although cholesterol crystals are known to act as danger signals in atherosclerosis, what primes IL-1β transcription remains elusive. Using a murine model of atherosclerosis, we found that cholesterol crystals acted both as priming and danger signals for IL-1β production. Cholesterol crystals triggered Neutrophils to release Neutrophil Extracellular Traps (NETs). NETs primed macrophages for cytokine release, activating T helper 17 (TH17) cells that amplify immune cell recruitment in atherosclerotic plaques. Therefore, danger signals may drive sterile inflammation, such as that seen in atherosclerosis, through their interactions with Neutrophils.
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inflammation Neutrophil Extracellular Traps license macrophages for cytokine production in atherosclerosis
Science, 2015Co-Authors: Annika Warnatsch, Marianna Ioannou, Qian Wang, Venizelos PapayannopoulosAbstract:Secretion of the cytokine interleukin-1β (IL-1β) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1β, and then endogenous "danger" signals activate innate immune signaling complexes called inflammasomes to process IL-1β for secretion. Although cholesterol crystals are known to act as danger signals in atherosclerosis, what primes IL-1β transcription remains elusive. Using a murine model of atherosclerosis, we found that cholesterol crystals acted both as priming and danger signals for IL-1β production. Cholesterol crystals triggered Neutrophils to release Neutrophil Extracellular Traps (NETs). NETs primed macrophages for cytokine release, activating T helper 17 (TH17) cells that amplify immune cell recruitment in atherosclerotic plaques. Therefore, danger signals may drive sterile inflammation, such as that seen in atherosclerosis, through their interactions with Neutrophils.
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Neutrophils sense microbe size and selectively release Neutrophil Extracellular Traps in response to large pathogens
Nature Immunology, 2014Co-Authors: Nora Anzk, Aleksandra Lubojemska, Sarah E Hardiso, Qia Wang, Maximiliano G Gutierrez, Venizelos PapayannopoulosAbstract:How Neutrophils clear hyphae and other pathogens that are too large to be ingested by phagocytosis has remained unknown. Papayannopoulos et al. show that Neutrophils sense microbe size and selectively release Neutrophil Extracellular Traps in response to large pathogens.
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Neutrophils sense microbe size and selectively release Neutrophil Extracellular Traps in response to large pathogens
Nature Immunology, 2014Co-Authors: Nora Branzk, Aleksandra Lubojemska, Maximiliano G Gutierrez, Qian Wang, Sarah E Hardison, Gordon D Brown, Venizelos PapayannopoulosAbstract:Neutrophils are critical for antifungal defense, but the mechanisms that clear hyphae and other pathogens that are too large to be phagocytosed remain unknown. We found that Neutrophils sensed microbe size and selectively released Neutrophil Extracellular Traps (NETs) in response to large pathogens, such as Candida albicans hyphae and Extracellular aggregates of Mycobacterium bovis, but not in response to small yeast or single bacteria. NETs were fundamental in countering large pathogens in vivo. Phagocytosis via dectin-1 acted as a sensor of microbe size and prevented NET release by downregulating the translocation of Neutrophil elastase (NE) to the nucleus. Dectin-1 deficiency led to aberrant NET release and NET-mediated tissue damage during infection. Size-tailored Neutrophil responses cleared large microbes and minimized pathology when microbes were small enough to be phagocytosed.
Arturo Zychlinsky - One of the best experts on this subject based on the ideXlab platform.
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Neutrophil Extracellular Traps the biology of chromatin externalization
Developmental Cell, 2018Co-Authors: Gabriel Sollberger, Dorothea Ogmore Tilley, Arturo ZychlinskyAbstract:Neutrophils are essential to the homeostatic mission of safeguarding host tissues, responding rapidly and diversely to breaches of the host's barriers to infection, and returning tissues to a sterile state. In response to specific stimuli, Neutrophils extrude modified chromatin structures decorated with specific cytoplasmic and granular proteins called Neutrophil Extracellular Traps (NETs). Several pathways lead to this unique form of cell death (NETosis). Extracellular chromatin may have evolved to defend eukaryotic organisms against infection, and its release has at least three functions: trapping and killing of microbes, amplifying immune responses, and inducing coagulation. Here we review Neutrophil development and heterogeneity with a focus on NETs, NET formation, and their relevance in host defense and disease.
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A proposed role for Neutrophil Extracellular Traps in cancer immunoediting.
Frontiers in immunology, 2013Co-Authors: Sivan Berger-achituv, Volker Brinkmann, Ulrike Abu Abed, Lars I. Kühn, Jonathan Ben-ezra, Ronit Elhasid, Arturo ZychlinskyAbstract:Upon activation, Neutrophils release fibers composed of chromatin and Neutrophil proteins termed Neutrophil Extracellular Traps (NETs). NETs trap and kill microbes, activate dendritic cells and T cells, and are implicated in autoimmune and vascular diseases. Given the growing interest in the role of Neutrophils in cancer immunoediting and the diverse function of NETs, we searched for NETs release by tumor-associated Neutrophils (TANs). Using pediatric Ewing sarcoma (ES) as a model, we retrospectively examined histopathological material from diagnostic biopsies of eight patients (mean ± SD age of 11.5 ± 4.7 years). TANs were found in six patients and in two of those we identified NETs. These two patients presented with metastatic disease and despite entering complete remission after intensive chemotherapy had an early relapse. NETs were not identified in the diagnostic biopsies of two patients with localized disease and two with metastatic disease. This study is the first to show that TANs in ES are activated to make NETs, pointing to a possible role of NETs in cancer.
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Neutrophil Extracellular Traps is immunity the second function of chromatin
Journal of Cell Biology, 2012Co-Authors: Volke Inkma, Arturo ZychlinskyAbstract:Neutrophil Extracellular Traps (NETs) are made of processed chromatin bound to granular and selected cytoplasmic proteins. NETs are released by white blood cells called Neutrophils, maybe as a last resort, to control microbial infections. This release of chromatin is the result of a unique form of cell death, dubbed “NETosis.” Here we review our understanding of how NETs are made, their function in infections and as danger signals, and their emerging importance in autoimmunity and coagulation.
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Neutrophil elastase and myeloperoxidase regulate the formation of Neutrophil Extracellular Traps
Journal of Cell Biology, 2010Co-Authors: Venizelos Papayannopoulos, Kathleen D Metzler, Abdul Hakkim, Arturo ZychlinskyAbstract:Neutrophils release decondensed chromatin termed Neutrophil Extracellular Traps (NETs) to trap and kill pathogens Extracellularly. Reactive oxygen species are required to initiate NET formation but the downstream molecular mechanism is unknown. We show that upon activation, Neutrophil elastase (NE) escapes from azurophilic granules and translocates to the nucleus, where it partially degrades specific histones, promoting chromatin decondensation. Subsequently, myeloperoxidase synergizes with NE in driving chromatin decondensation independent of its enzymatic activity. Accordingly, NE knockout mice do not form NETs in a pulmonary model of Klebsiella pneumoniae infection, which suggests that this defect may contribute to the immune deficiency of these mice. This mechanism provides for a novel function for serine proteases and highly charged granular proteins in the regulation of chromatin density, and reveals that the oxidative burst induces a selective release of granular proteins into the cytoplasm through an unknown mechanism.
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Neutrophil Extracellular Traps how to generate and visualize them
Journal of Visualized Experiments, 2010Co-Authors: Volker Brinkmann, Christian Goosmann, Ulrike Abu Abed, Britta Laube, Arturo ZychlinskyAbstract:Neutrophil granulocytes are the most abundant group of leukocytes in the peripheral blood. As professional phagocytes, they engulf bacteria and kill them intracellularly when their antimicrobial granules fuse with the phagosome. We found that Neutrophils have an additional way of killing microorganisms: upon activation, they release granule proteins and chromatin that together form Extracellular fibers that bind pathogens. These novel structures, or Neutrophil Extracellular Traps (NETs), degrade virulence factors and kill bacteria, fungi and parasites. The structural backbone of NETs is DNA, and they are quickly degraded in the presence of DNases. Thus, bacteria expressing DNases are more virulent. Using correlative microscopy combining TEM, SEM, immunofluorescence and live cell imaging techniques, we could show that upon stimulation, the nuclei of Neutrophils lose their shape and the eu- and heterochromatin homogenize. Later, the nuclear envelope and the granule membranes disintegrate allowing the mixing of NET components. Finally, the NETs are released as the cell membrane breaks. This cell death program (NETosis) is distinct from apoptosis and necrosis and depends on the generation of Reactive Oxygen Species by NADPH oxidase. Neutrophil Extracellular Traps are abundant at sites of acute inflammation. NETs appear to be a form of innate immune response that bind microorganisms, prevent them from spreading, and ensure a high local concentration of antimicrobial agents to degrade virulence factors and kill pathogens thus allowing Neutrophils to fulfill their antimicrobial function even beyond their life span. There is increasing evidence, however, that NETs are also involved in diseases that range from auto-immune syndromes to infertility. We describe methods to isolate Neutrophil Granulocytes from peripheral human blood and stimulate them to form NETs. Also we include protocols to visualize the NETs in light and electron microscopy.
Paul Kubes - One of the best experts on this subject based on the ideXlab platform.
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Neutrophils and Neutrophil Extracellular Traps in the liver and gastrointestinal system
Nature Reviews Gastroenterology & Hepatology, 2018Co-Authors: Masaki Honda, Paul KubesAbstract:Neutrophil Extracellular Traps (NETs) have an important role during infection but they are also related to the exacerbation of inflammation and the development of autoimmunity, cancer metastasis and inappropriate thrombosis. Here, the authors focus on the role of NETs in the liver and gastrointestinal system, outlining their protective and pathological effects and their potential for therapeutic intervention.
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Neutrophils and Neutrophil Extracellular Traps in the liver and gastrointestinal system
Nature Reviews Gastroenterology & Hepatology, 2018Co-Authors: Masaki Honda, Paul KubesAbstract:Neutrophil Extracellular Traps (NETs) have an important role during infection by helping Neutrophils to capture and kill pathogens. However, evidence is accumulating that uncontrolled or excessive production of NETs is related to the exacerbation of inflammation and the development of autoimmunity, cancer metastasis and inappropriate thrombosis. In this Review, we focus on the role of NETs in the liver and gastrointestinal system, outlining their protective and pathological effects. The latest mechanistic insights in NET formation, interactions between microorganisms and NETs and the relationship between Neutrophil subtypes and their functions are also discussed. Additionally, we describe the potential importance of NET-related molecules, including cell-free DNA and hypercitrullinated histones, as biomarkers and targets for therapeutic intervention in gastrointestinal diseases.
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an emerging role for Neutrophil Extracellular Traps in noninfectious disease
Nature Medicine, 2017Co-Authors: Selina K Jorch, Paul KubesAbstract:The production of Neutrophil Extracellular Traps (NETs) is a process that enables Neutrophils to help catch and kill bacteria. However, increasing evidence suggests that this process might also occur in noninfectious, sterile inflammation. In this Review, we describe the role of NETosis in autoimmunity, coagulation, acute injuries and cancer, and discuss NETs as potential therapeutic targets. Furthermore, we consider whether Extracellular DNA is always detrimental in sterile inflammation and whether the source is always NETs.
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Neutrophil Extracellular Traps sequester circulating tumor cells and promote metastasis
Journal of Clinical Investigation, 2013Co-Authors: Jonathan Coolslartigue, Paul Kubes, Jonathan Spicer, Braedon Mcdonald, Stephen Gowing, Simon C Chow, Betty Giannias, Lorenzo E FerriAbstract:The majority of patients with cancer undergo at least one surgical procedure as part of their treatment. Severe postsurgical infection is associated with adverse oncologic outcomes; however, the mechanisms underlying this phenomenon are unclear. Emerging evidence suggests that Neutrophils, which function as the first line of defense during infections, facilitate cancer progression. Neutrophil Extracellular Traps (NETs) are Extracellular Neutrophil-derived DNA webs released in response to inflammatory cues that trap and kill invading pathogens. The role of NETs in cancer progression is entirely unknown. We report that circulating tumor cells become trapped within NETs in vitro under static and dynamic conditions. In a murine model of infection using cecal ligation and puncture, we demonstrated microvascular NET deposition and consequent trapping of circulating lung carcinoma cells within DNA webs. NET trapping was associated with increased formation of hepatic micrometastases at 48 hours and gross metastatic disease burden at 2 weeks following tumor cell injection. These effects were abrogated by NET inhibition with DNAse or a Neutrophil elastase inhibitor. These findings implicate NETs in the process of cancer metastasis in the context of systemic infection and identify NETs as potential therapeutic targets.
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intravascular Neutrophil Extracellular Traps capture bacteria from the bloodstream during sepsis
Cell Host & Microbe, 2012Co-Authors: Braedon Mcdonald, Rossana Urrutia, Bryan G Yipp, Craig N Jenne, Paul KubesAbstract:During the systemic inflammatory response of severe sepsis, Neutrophils accumulate in the liver microcirculation, but their functional significance is largely unknown. We show that Neutrophils migrate to liver sinusoids during endotoxemia and sepsis where they exert protective effects by releasing Neutrophil Extracellular Traps (NETs), which are DNA-based structures that capture and eliminate microbes. NETs released into the vasculature ensnare bacteria from the bloodstream and prevent dissemination. NET production requires platelet-Neutrophil interactions and can be inhibited by platelet depletion or disruption of integrin-mediated platelet-Neutrophil binding. During sepsis, NET release increases bacterial trapping by 4-fold (beyond the basal level provided by resident intravascular macrophages). Blocking NET formation reduces the capture of circulating bacteria during sepsis, resulting in increased dissemination to distant organs. Thus, NETs ensnare circulating bacteria and provide intravascular immunity that protects against bacterial dissemination during septic infections.
Simon F De Meyer - One of the best experts on this subject based on the ideXlab platform.
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Neutrophil Extracellular Traps in arterial and venous thrombosis
Seminars in Thrombosis and Hemostasis, 2019Co-Authors: Elodie Laridan, Kimberly Martinod, Simon F De MeyerAbstract:Thrombotic complications are still a major health risk worldwide. Our view on the pathophysiology of thrombosis has significantly changed since the discovery of Neutrophil Extracellular Traps (NETs) and their prothrombotic characteristics. Generated by Neutrophils that release their decondensed chromatin as a network of Extracellular fibers, NETs promote thrombus formation by serving as a scaffold that activates platelets and coagulation. The thrombogenic involvement of NETs has been described in various settings of thrombosis, including stroke, myocardial infarction, and deep vein thrombosis. The aim of this review is to summarize existing evidence showing the presence of NETs in human thrombus material. Following an introduction on NETs and their role in thrombus formation, the authors address studies showing the presence of NETs in arterial or venous thrombi. In addition, they focus on potential novel therapeutic opportunities to resolve or prevent thrombosis by targeting NETs.
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Neutrophil Extracellular Traps in ischemic stroke thrombi
Annals of Neurology, 2017Co-Authors: Elodie Laridan, Frederik Denorme, Linda Desender, Olivier Francois, Tommy B Andersson, Hans Deckmyn, Karen Vanhoorelbeke, Simon F De MeyerAbstract:Objective: Neutrophil Extracellular Traps (NETs) have been shown to promote thrombus formation. Little is known about the exact composition of thrombi that cause ischemic stroke. In particular no information is yet available on the presence of NETs in cerebral occlusions. Such information is however essential to improve current thrombolytic therapy with t-PA. This study aimed at investigating the presence of Neutrophils and more specifically NETs in ischemic stroke thrombi. Methods: Sixty-eight thrombi retrieved from ischemic stroke patients undergoing endovascular treatment were characterized by immunostaining using Neutrophil markers (CD66b and Neutrophil elastase) and NETs markers (citrullinated histones H3 (H3Cit) and Extracellular DNA). Neutrophils and NETs were quantified. In addition, Extracellular DNA was targeted by performing ex vivo lysis of retrieved thrombi with DNase 1 and t-PA. Results: Neutrophils were detected extensively throughout all thrombi. Citrullinated histones H3 (H3Cit), a hallmark of NETs, were observed in almost all thrombi. H3Cit-positive area varied up to 13.45% of total thrombus area. Co-localization of H3Cit with Extracellular DNA released from Neutrophils confirmed the specific presence of NETs. H3Cit was more abundant in thrombi from cardioembolic origin compared to other etiologies. Older thrombi contained significantly more Neutrophils and H3Cit compared to fresh thrombi. Interestingly, ex vivo lysis of patient thrombi was more successful when adding DNase 1 to standard t-PA. Interpretation: Neutrophils and NETs form important constituents of cerebral thrombi. Targeting of NETs with DNase 1 might have prothrombolytic potential in treatment of acute ischemic stroke. This article is protected by copyright. All rights reserved.
Volker Brinkmann - One of the best experts on this subject based on the ideXlab platform.
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Neutrophil Extracellular Traps in the second decade
Journal of Innate Immunity, 2018Co-Authors: Volker BrinkmannAbstract:Nearly 15 years after the first description of Neutrophil Extracellular Traps (NETs), our knowledge concerning this structure has expanded considerably. Initially, NETs were considered solely an elaborate function of the innate immune system to combat invading microorganisms. Successively it became clear that NETs have farther-reaching capabilities. They are involved in a series of pathophysiological mechanisms ranging from inflammation to thrombosis where they fulfill essential functions when produced at the right site and the right time but can have a serious impact when generation or clearance of NETs is inadequately controlled. This review provides a concise overview on the far-reaching functions of NETs in health and disease.
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cell cycle proteins control production of Neutrophil Extracellular Traps
Developmental Cell, 2017Co-Authors: Borko Amulic, Volker Brinkmann, Sebastian Lorenz Knackstedt, Ulrike Abu Abed, Nikolaus Deigendesch, Christopher J Harbort, Brian E Caffrey, Frank L Heppner, Philip W HindsAbstract:Neutrophils are essential for immune defense and can respond to infection by releasing chromatin in the form of Neutrophil Extracellular Traps (NETs). Here we show that NETs are induced by mitogens and accompanied by induction of cell-cycle markers, including phosphorylation of the retinoblastoma protein and lamins, nuclear envelope breakdown, and duplication of centrosomes. We identify cyclin-dependent kinases 4 and 6 (CDK4/6) as essential regulators of NETs and show that the response is inhibited by the cell-cycle inhibitor p21Cip. CDK6, in Neutrophils, is required for clearance of the fungal pathogen Candida albicans. Our data describe a function for CDK4/6 in immunity.
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A proposed role for Neutrophil Extracellular Traps in cancer immunoediting.
Frontiers in immunology, 2013Co-Authors: Sivan Berger-achituv, Volker Brinkmann, Ulrike Abu Abed, Lars I. Kühn, Jonathan Ben-ezra, Ronit Elhasid, Arturo ZychlinskyAbstract:Upon activation, Neutrophils release fibers composed of chromatin and Neutrophil proteins termed Neutrophil Extracellular Traps (NETs). NETs trap and kill microbes, activate dendritic cells and T cells, and are implicated in autoimmune and vascular diseases. Given the growing interest in the role of Neutrophils in cancer immunoediting and the diverse function of NETs, we searched for NETs release by tumor-associated Neutrophils (TANs). Using pediatric Ewing sarcoma (ES) as a model, we retrospectively examined histopathological material from diagnostic biopsies of eight patients (mean ± SD age of 11.5 ± 4.7 years). TANs were found in six patients and in two of those we identified NETs. These two patients presented with metastatic disease and despite entering complete remission after intensive chemotherapy had an early relapse. NETs were not identified in the diagnostic biopsies of two patients with localized disease and two with metastatic disease. This study is the first to show that TANs in ES are activated to make NETs, pointing to a possible role of NETs in cancer.
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Neutrophil Extracellular Traps how to generate and visualize them
Journal of Visualized Experiments, 2010Co-Authors: Volker Brinkmann, Christian Goosmann, Ulrike Abu Abed, Britta Laube, Arturo ZychlinskyAbstract:Neutrophil granulocytes are the most abundant group of leukocytes in the peripheral blood. As professional phagocytes, they engulf bacteria and kill them intracellularly when their antimicrobial granules fuse with the phagosome. We found that Neutrophils have an additional way of killing microorganisms: upon activation, they release granule proteins and chromatin that together form Extracellular fibers that bind pathogens. These novel structures, or Neutrophil Extracellular Traps (NETs), degrade virulence factors and kill bacteria, fungi and parasites. The structural backbone of NETs is DNA, and they are quickly degraded in the presence of DNases. Thus, bacteria expressing DNases are more virulent. Using correlative microscopy combining TEM, SEM, immunofluorescence and live cell imaging techniques, we could show that upon stimulation, the nuclei of Neutrophils lose their shape and the eu- and heterochromatin homogenize. Later, the nuclear envelope and the granule membranes disintegrate allowing the mixing of NET components. Finally, the NETs are released as the cell membrane breaks. This cell death program (NETosis) is distinct from apoptosis and necrosis and depends on the generation of Reactive Oxygen Species by NADPH oxidase. Neutrophil Extracellular Traps are abundant at sites of acute inflammation. NETs appear to be a form of innate immune response that bind microorganisms, prevent them from spreading, and ensure a high local concentration of antimicrobial agents to degrade virulence factors and kill pathogens thus allowing Neutrophils to fulfill their antimicrobial function even beyond their life span. There is increasing evidence, however, that NETs are also involved in diseases that range from auto-immune syndromes to infertility. We describe methods to isolate Neutrophil Granulocytes from peripheral human blood and stimulate them to form NETs. Also we include protocols to visualize the NETs in light and electron microscopy.
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mouse Neutrophil Extracellular Traps in microbial infections
Journal of Innate Immunity, 2009Co-Authors: David Ermert, Arturo Zychlinsky, Christian Goosmann, Britta Laube, Constantin F Urban, Volker BrinkmannAbstract:Neutrophil Extracellular Traps (NETs) play an important role in innate immunity to microbial infections. NETs have been described in several species, but the molecular details of NET formation and their role in infection has not been addressed, partly because we lack optimal experimental models. Here we describe tools to investigate NET formation in Neutrophils isolated from mice. Upon in vitro stimulation of wild-type mouse Neutrophils with PMA, we analyzed 3 important steps in the process of NET formation: reactive oxygen species (ROS) production, NET cell death and NET release. As expected, Neutrophils from NADPH oxidase-deficient mice failed to produce ROS and did not die nor release NETs upon stimulation. We found that Neutrophils from several mouse strains produced NETs with different efficiency and that NET formation correlated with the amount of ROS produced. Activation with Candida albicans also resulted in ROS production and NET cell death. The hyphal form of this fungus induced NETs more effectively than the yeast form. With this work, we provide tools to study in vitro NET assembly in the mouse system.