The clinical value of neutrophil extracellular traps

Lögters, Tim; Margraf, Stefan; Altrichter, Jens; Činátl, Jindřich; Mitzner, Steffen; Windolf, Joachim; Scholz, Martin

doi:10.1007/s00430-009-0121-x

Cited by 101 publications

(100 citation statements)

References 65 publications

(99 reference statements)

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“…NETs are extracellular chromatin fibers bound to granular, nuclear and cytoplasmic proteins that despite their importance as effective antimicrobial first line defense mechanism, also occur in various clinical settings in the absence of microbial infections and might be associated with pathophysiological conditions (Logters et al, 2009). In a previous study (Naegele et al, 2012), we demonstrated that neutrophils in RRMS patients are more numerous and exhibit a primed state.…”

Section: -Discussionmentioning

confidence: 99%

“…NETs not only trap and kill pathogens very efficiently but also minimize collateral tissue damage by containing proteases to the DNA fibers and act as physical barriers preventing microbial spread. Despite the well documented importance of NETs as an effective antimicrobial first line defense mechanism, there is increasing evidence that NETs occur in various clinical settings in the absence of microbial infections and that they are probably also associated with pathophysiological conditions (Amulic et al, 2012;Logters et al, 2009). NETosis, the process of neutrophil cell death that leads to expulsion of NETs, can be triggered by different stimuli including pro-inflammatory cytokines such as IL-8 and TNFα, phorbol 12-myristate 13-acetate (PMA) (Brinkmann et al, 2004;Fuchs et al, 2007), activated platelets (Clark et al, 2007) and endothelial cells (Gupta et al, 2010), and placental microparticles (Gupta et al, 2005).…”

Section: -Introductionmentioning

confidence: 99%

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Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

Tillack

Naegele

Haueis

et al. 2013

Journal of Neuroimmunology

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Neutrophil extracellular traps (NETs) trap and kill pathogens very efficiently but also activate dendritic cells and prime T cells. Previously, we demonstrated that neutrophils are primed and circulating NETs are elevated in relapsing remitting multiple sclerosis (RRMS), a T cell-mediated autoimmune disease. Here, we demonstrate gender specific differences in circulating NETs but not in neutrophil priming in RRMS patients. Although the results from our systematic and in depth characterization of these patients argue against a major role of circulating NETs in this disease, they suggest that NETs may underlie gender-specific differences in MS pathogenesis. Abstract (100 words)Neutrophil extracellular traps (NETs) trap and kill pathogens very efficiently but also activate dendritic cells and prime T cells. Previously, we demonstrated that neutrophils are primed and circulating NETs are elevated in relapsing remitting multiple sclerosis (RRMS), a T cell-mediated autoimmune disease. Here, we demonstrate gender specific differences in circulating NETs but not in neutrophil priming in RRMS patients. Although the results from our systematic and in depth characterization of these patients argue against a major role of circulating NETs in this disease, they suggest that NETs may underlie gender-specific differences in MS pathogenesis.Key words: Neutrophil, neutrophil extracellular traps (NETs), multiple sclerosis, genderCirculating NETs in MS patients 3 1-IntroductionThe main function of the innate immune system during infection is to eliminate the pathogen, and neutrophils are key players in innate immune responses.Women of reproductive age are more resistant to sepsis and subsequent morbidity and mortality than men (Schroder et al., 1998), and the incidence of sepsis in postmenopausal women increases to levels almost equal to those seen in age-matched men (Martin et al., 2003). Women also have a higher systemic neutrophil count compared with men (Bain and England, 1975a), and neutrophil counts correlate with estradiol levels during menstruation (Bain and England, 1975b) and pregnancy (Efrati et al., 1964) suggesting that sex hormones influence neutrophilia and overall resistance to sepsis most likely by delaying apoptosis in neutrophils (Molloy et al., 2003). In order to eliminate pathogens during infections, neutrophils are armed with a variety of weapons including engulfment and intracellular degradation of microbes (Hampton et al., 1998;Segal, 2005), release of oxygen species and granule proteins (Lehrer and Ganz, 1999) and release of extracellular chromatin fibers bound to granular, nuclear and cytoplasmic proteins called neutrophil extracellular traps (NETs) (Brinkmann et al., 2004). NETs not only trap and kill pathogens very efficiently but also minimize collateral tissue damage by containing proteases to the DNA fibers and act as physical barriers preventing microbial spread. Despite the well documented importance of NETs as an effective antimicrobial first line defense mechanism, there is increasing ...

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Section: -Discussionmentioning

confidence: 99%

Section: -Introductionmentioning

confidence: 99%

Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

Tillack

Naegele

Haueis

et al. 2013

Journal of Neuroimmunology

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“…MCETs are also composed of nuclear histones and the antimicrobial cathelicidin LL37, as well as tryptase, a granular mast cell marker (Supplementary Table 1). 20 Although extracellular trap formation was shown to occur in various clinical conditions (Table 1), 22 it remains unclear whether cell death per se is required for the release of NETs in vivo, as we will discuss below.…”

Section: Release Of Extracellular Trapsmentioning

confidence: 99%

Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality

et al. 2011

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Neutrophil extracellular traps (NETs) are chromatin structures loaded with antimicrobial molecules. They can trap and kill various bacterial, fungal and protozoal pathogens, and their release is one of the first lines of defense against pathogens. In vivo, NETs are released during a form of pathogen-induced cell death, which was recently named NETosis. Ex vivo, both dead and viable neutrophils can be stimulated to release NETs composed of either nuclear or mitochondrial chromatin, respectively. In certain pathological conditions, NETs are associated with severe tissue damage or certain auto-immune diseases. This review describes the recent progress made in the identification of the mechanisms involved in NETosis and discusses its interplay with autophagy and apoptosis. Cell Death and Differentiation (2011) 18, 581-588; doi:10.1038/cdd.2011.1; published online 4 February 2011Neutrophils have an essential role in innate immunity and are the first cells recruited to the site of infection.1 Human neutrophils are the most abundant leukocytes. They have a very short lifespan, and neutrophil homeostasis is maintained by continuous release of many neutrophils from the bone marrow. Accelerated neutrophil death decreases neutrophil counts (neutropenia) and increases susceptibility to infection. In turn, delayed neutrophil death increases neutrophil counts (neutrophilia) and intensifies innate defenses, possibly promoting chronic inflammation.2 Neutrophils perform their function by engulfing microorganisms or opsonized particles and degrading them by various molecules, and also release lytic enzymes that destroy extracellular pathogens.3 Moreover, they release structures called neutrophil extracellular traps (NETs) that can trap and kill microbes. 4 The neutrophil lifespan constitutes a sensitive balance between their function as effecter cells and their potential to inflict tissue damage. In the absence of inflammatory stimuli, neutrophils continuously undergo apoptosis within 24-48 h both in vivo and in cell culture. The large amounts of superoxide produced by the membrane-associated NADPH oxidase in neutrophils have a central role in the destruction of invading pathogens as well as in the resolution of inflammation. [5][6][7][8][9] Congenital defects that prevent NADPH oxidase activity result in chronic granulomatous disease (CGD), which is characterized by exaggerated immune responses 10 and recurrent life-threatening infections by a narrow set of microorganisms. 11 We recently found that formation of NETs by activated neutrophils requires not only NADPH-oxidasemediated superoxide production, but also autophagy. 12In this review, we present an overview of the main biochemical and morphological features observed during neutrophil activation and discuss in more detail the contribution of NADPH oxidase, histone citrullination, intracellular calcium levels and autophagy to chromatin decondensation and NET formation. Release of Extracellular TrapsIn 2004, the group of Brinkman and Zychlinsky was the first to report the rele...

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“…It was also reported that NETs in capillary vessels might be related to the pathophysiology of disseminated intravascular coagulation. 19 Although NETs have been extensively studied, [2][3][4][5][6][7][8][9][10] it has been difficult to evaluate NET formation in clinical specimens. The authors have previously reported that purulent sputum from patients with acute respiratory infections contained abundant NETs, the amount of which gradually decreased as the clinical symptoms and inflammation subsided.…”

Section: Introductionmentioning

confidence: 99%

Identification of neutrophil extracellular traps in the blood of patients with systemic inflammatory response syndrome

et al. 2013

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Objective: Neutrophils are able to form 'neutrophil extracellular traps' (NETs), which they use to trap and kill pathogens such as bacteria and fungi at the foci of infection. This observational study investigated the presence of NETs in the blood from critically ill patients and healthy volunteers. Methods: Fluorescent triple-colour immunocytochemical analysis of blood smears collected from patients with systemic inflammatory response syndrome (SIRS; associated with various clinical conditions) who had been hospitalized in the intensive care unit, and healthy volunteers, was undertaken to identify NETs in the blood. Blood smears were stained for DNA, histone H1 and neutrophil elastase. Results: NETs were identified in 10 of 21 (47.6%) blood samples from the study group compared with none of the blood samples from eight healthy volunteers. Conclusion: These data suggest that fluorescent triple-colour immunocytochemical staining of NETs in the blood could be used to simplify the early identification of critically ill patients with SIRS.

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The clinical value of neutrophil extracellular traps

Cited by 101 publications

References 65 publications

Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality

Identification of neutrophil extracellular traps in the blood of patients with systemic inflammatory response syndrome

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