Age is the work of art? Impact of neutrophil and organism age on neutrophil extracellular trap formation

Ortmann, Weronika; Kołaczkowska, Elżbieta

doi:10.1007/s00441-017-2751-4

Cited by 63 publications

(58 citation statements)

References 195 publications

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“…The next two articles address the various effector functions of neutrophils (Yin and Heit 2018;Ortmann and Kolaczkowska 2018). Neutrophils possess a diverse array of Btools^with which they can use to deal with infectious agents or injured tissue.…”

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confidence: 99%

Neutrophils: multitasking first responders of immunity and tissue homeostasis

2018

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From an evolutionary perspective, neutrophils are one of oldest immune cell types and represent a key first responder to infection and tissue injury (Leiding 2017). These early immune components first appear in simple invertebrates, such as cnidarians, as cells called amebocytes. In higher invertebrates, these primordial neutrophils take the form of hemocytes, cells that possess many of the functions of both neutrophils (phagocytosis, degranulation) and platelets (ability to initiate clotting of hemolymph). In vertebrates, these frontline immune cells take the form of the classic neutrophil, a granular phagocyte that is rapidly recruited to sites of infection or injury. Diverging from its evolutionary roots, the vertebrate neutrophil has lost much of its hemostatic function and appears to be dedicated to the host response to infection/injury.In many ways, the rapid and robust response of neutrophils to infection has placed this leukocyte in the spotlight as the prototypical cell of the innate immune response. Upon infection or injury, neutrophils are recruited en masse, migrating from the bloodstream, crossing the endothelium, and entering the tissue interstitium where these cells then home to the specific site of challenge. Over the past century, these foot soldiers of the innate immune system have been studied in detail, providing great insight as to how the host recognizes pathogens, how cells are recruited to specific tissue beds, how immune cells are able to directly kill a variety of pathogens (lysosomes, proteases, reactive-oxygen species), and how immune cells inflict the collateral damage associated with inflammation. These studies began to define a clear role for the neutrophil as a short lived, non-discriminating killer that, while key to controlling infectious agents, often resulted in significant harm to self-tissues in an effort to ensure the clearance of the pathogen. For decades, this view of neutrophils as an unsophisticated Bthug^of the innate immune system predominated, and, for the most part, limited efforts to search for, and understand, other functions of the neutrophil.Despite the common view that we had already fully mapped the function of the neutrophil, research persisted and, with the advent of new techniques and technology (conditional genetic knock-out animals, blocking and depleting antibodies, multi-color flow cytometry, etc.), our understanding of these prototypical innate immune cells has changed dramatically over the last two decades. In particular, perhaps no single technique has advanced our understanding of neutrophils biology better than intravital imaging. What began with Julius Cohnheim nearly 150 years ago, using a simple white-light microscope to study blood flow and leukocyte behavior in a frog's tongue, has evolved to embrace cuttingedge technology allowing for the visualization multiple cell types, pathogens, and effector functions in real-time, in the living animal with resolution never believed to be possible. With this approach we have mapped cell recruitment, adhe...

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confidence: 99%

Neutrophils: multitasking first responders of immunity and tissue homeostasis

2018

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“…Other cell death mechanisms also lead to the release of cfDNA into the extracellular space, but programmed cell death mechanisms (such as apoptosis) may take longer periods of time as our measurement intervals of 3 h (35). Higher levels of DNA release upon increased individuals' age could be explained by the elevated number of immature, newly released neutrophils that were previously reported to release their DNA also spontaneously (36,37), regardless of the stimulus or the respective concentrations.…”

Section: Discussionmentioning

confidence: 93%

“…While DNA release was high in AG2 as well as AG3 (frequently exhibiting comparable median levels, see Figure 2), the NET marker H3Cit was highest in the middle aged group of 45-54 years (in baseline, unstimulated and IO stimulated samples). Considering the lower level of H3Cit positive LDNs in AG3, it could be argued that older people have higher numbers of immature neutrophils that most likely have released their NETs spontaneously in circulation and therefore could not be activated again ex vivo (36,37). Another potential explanation for this discrepancy is that neutrophils may change to another pathway of NET induction, without the generation of H3Cit.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Age-related changes of neutrophil characteristics, potential of activation, DNA release and NET formation

Krall

Mauracher

Roiß

et al. 2020

Preprint

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Background: Neutrophils are a heterogeneous population of leukocytes, which can be subdivided into high and low density neutrophils (HDNs/LDNs). They are known to fight intruders with different mechanisms, including the release of neutrophil extracellular traps (NETs), which have also been associated with thrombosis. Risks of infection and thrombosis increase with age. Differences in neutrophil subpopulations and functionality have been shown in various disease states, but investigations in healthy subjects and their dependence on age are lacking. The aim of this study was to investigate age-related changes in neutrophils regarding neutrophil subpopulations, their potential of activation, DNA release and NET formation.Methods: Neutrophil subpopulations (HDNs and LDNs) were isolated from 25 healthy individuals subdivided into 3 groups (<45 years, n=8; 45-54, n=9; >54, n=8). Neutrophil characteristics, potential of activation and the ability of NET formation was investigated using flow cytometry. Externalisation of DNA was detected by a DNA release assay.Results: HDN and LDN counts did not differ between age-groups. However, with increasing age we observed a shift in neutrophil subpopulations towards a lower amount of mature LDNs, characterized by their expression of membrane receptors CD62L and CD16. Upon stimulation, neutrophils of older individuals showed significantly higher release of DNA. HDNs of younger participants increased activation markers (CD66b and CD11b) to a higher extent compared to those of older individualsConclusion: Neutrophils and their ability of activation, DNA release and NET formation change with age and this might contribute to the higher risk of infection and thrombosis at advanced age. Furthermore, these results highlight the importance and necessity of age-matching in studies that focus on neutrophil characteristics.

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“…Nevertheless, the decreased Accordingly, more studies are necessary to elucidate potential differences in NET formation in different microenvironments. Neutrophils of elderly human seem to release less NETs than those of young individuals (32). In our cohort, we included more controls and these were not strictly age and gender matched to the patients with sepsis.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular trap formation and nuclease activity in septic patients

Cox

Walstein

Völlger

et al. 2019

Preprint

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Background: There is little knowledge, whether in patients with sepsis neutrophil extracellular trap (NET) formation and NET degrading nuclease activity are altered. Thus, we tested the hypotheses that 1) NET formation from neutrophils of septic patients is increased compared to healthy volunteers, both without stimulation and following incubation with mitochondrial DNA (mtDNA), a damage-associated molecular pattern, or phorbol 12-myristate 13-acetate (PMA; positive control); and 2) serum nuclease activities are increased as well. Methods: We included 18 septic patients and 27 volunteers in this prospective observational trial while study was registered retrospectively. Blood was withdrawn and NET formation from neutrophils in vitro was quantified (average percentage of neutrophils showing NET formation on an image) without stimulation and following incubation with mtDNA (10µg/well) or PMA (25nmol). Serum nuclease activity was assessed using gel electrophoresis. Results: In contrast to our hypothesis, compared to healthy volunteers unstimulated NET release from neutrophils in septic patients was decreased by 46.3% (4.3%±1.8 SD vs. 8.2%±2.9, p≤0.0001) and 48.1% (4.9%±2.5 vs. 9.4%±5.2, p=0.002) after 2 and 4 hours of incubation. mtDNA further decreased NET formation in neutrophils from septic patients (4.7%±1.2 to 2.8%±0,8; p=0.03) but did not alter NET formation in neutrophils from volun-teers. As expected, PMA, as positive control, increased NET formation to 73.2% (±29.6) in septic patients and to 91.7% (±7.1) in volunteers after 4 hours of incubation (p=0.22). Serum nuclease activity (range: 0-6) was decreased in septic patients by 39.6% (3±2 vs 5±0; median and ICR, p=0.0001) compared to volunteers. Conclusions: Unstimulated NET formation and nuclease activity are decreased in septic patients and mtDNA can further reduce NET formation. Thus, neutrophils from septic patients show decreased NET formation in vitro despite diminished nuclease activity in vivo. Trail registration DRKS00007694, German Clinical Trials database (DRKS). Registered retrospectively 06.02.2015.

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Age is the work of art? Impact of neutrophil and organism age on neutrophil extracellular trap formation

Cited by 63 publications

References 195 publications

Neutrophils: multitasking first responders of immunity and tissue homeostasis

Neutrophils: multitasking first responders of immunity and tissue homeostasis

WITHDRAWN: Age-related changes of neutrophil characteristics, potential of activation, DNA release and NET formation

Neutrophil extracellular trap formation and nuclease activity in septic patients

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