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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 39841

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Special Issue Editor

Dr. Milladur Rahman

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Guest Editor

Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden
Interests: inflammation; sepsis; pancreatitis; lung; neutrophils infiltration; platelets; endothelium; chemokines; NETosis, microRNA

Special Issue Information

Dear Colleagues,

Neutrophils act as the body’s first line of defense against invading infectious agents such as bacteria, fungi, and protozoa. In response to chemoattractant stimuli, neutrophils migrate from blood vessels to the site of infection and attack the invading pathogens by releasing proteolytic enzymes and antimicrobial proteins. In addition to their classical function, neutrophils are known to trap and kill pathogens by releasing web-like structures called neutrophil extracellular trap (NET). Although NET is part of the host defense mechanism, it is known to contribute in the pathogenesis of various inflammatory diseases such as vascular disorder, inflammatory lung diseases, acute pancreatitis, cancer, as well as in autoimmune disease such as rheumatoid arthritis and systemic lupus erythematous. The mechanism of NET formation is complex and remains to be elucidated despite a large number of studies having shown the basic mechanisms of NET formation. In addition, an effective therapeutic strategy targeting NET formation in various inflammatory diseases is yet to be devised. In this Special Issue of IJMS, I invite you to contribute original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Molecular Research on Neutrophil Extracellular Trap (NET)”. Expert articles describing immunopathology, intracellular signaling, extracellular stimuli, or general aspects of NET-mediated tissue damage in different disease conditions are highly welcome.

Dr. Milladur Rahman
Guest Editor

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Keywords

Neutrophil extracellular traps
Signaling pathways
Inflammatory diseases
In vitro and in vivo models
Innate immune dysregulation
Translational medicine
Therapeutic targets
Autoimmune diseases
Vascular disorder

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Published Papers (5 papers)

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17 pages, 684 KiB

Open AccessReview

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease

by Johannes Klopf, Christine Brostjan, Wolf Eilenberg and Christoph Neumayer

Int. J. Mol. Sci. 2021, 22(2), 559; https://doi.org/10.3390/ijms22020559 - 8 Jan 2021

Cited by 146 | Viewed by 16872

Abstract

Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient’s immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches. Full article

(This article belongs to the Special Issue Molecular Research on Neutrophil Extracellular Trap (NET))

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10 pages, 21852 KiB

Open AccessArticle

Effects of Thrombomodulin in Reducing Lethality and Suppressing Neutrophil Extracellular Trap Formation in the Lungs and Liver in a Lipopolysaccharide-Induced Murine Septic Shock Model

by Yu Kato, Osamu Nishida, Naohide Kuriyama, Tomoyuki Nakamura, Takahiro Kawaji, Takanori Onouchi, Daisuke Hasegawa and Yasuyo Shimomura

Int. J. Mol. Sci. 2021, 22(9), 4933; https://doi.org/10.3390/ijms22094933 - 6 May 2021

Cited by 14 | Viewed by 3076

Abstract

Neutrophil extracellular trap (NET) formation, an innate immune system response, is associated with thrombogenesis and vascular endothelial injury. Circulatory disorders due to microvascular thrombogenesis are one of the principal causes of organ damage. NET formation in organs contributes to the exacerbation of sepsis, which is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. We have previously reported that recombinant human soluble thrombomodulin (rTM) reduces lipopolysaccharide (LPS)-induced NET formation in vitro. Here, we aimed to show that thrombomodulin (TM)-mediated suppression of NET formation protects against organ damage in sepsis. Mice were injected intraperitoneally (i.p.) with 10 mg/kg LPS. rTM (6 mg/kg/day) or saline was administered i.p. 1 h after LPS injection. In the LPS-induced murine septic shock model, extracellular histones, which are components of NETs, were observed in the liver and lungs. In addition, the serum cytokine (interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage chemotactic protein-1 (MCP-1), and interleukin-10 (IL-10)) levels were increased. The administration of rTM in this model prevented NET formation in the organs and suppressed the increase in the levels of all cytokines except IL-1β. Furthermore, the survival rate improved. We provide a novel role of TM in treating inflammation and NETs in organs during sepsis. Full article

(This article belongs to the Special Issue Molecular Research on Neutrophil Extracellular Trap (NET))

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18 pages, 1780 KiB

Open AccessReview

Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis

by Umama Khan, Sabrina Chowdhury, Md Morsaline Billah, Kazi Mohammed Didarul Islam, Henrik Thorlacius and Milladur Rahman

Int. J. Mol. Sci. 2021, 22(14), 7260; https://doi.org/10.3390/ijms22147260 - 6 Jul 2021

Cited by 55 | Viewed by 10187

Abstract

Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy. Full article

(This article belongs to the Special Issue Molecular Research on Neutrophil Extracellular Trap (NET))

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23 pages, 3106 KiB

Open AccessArticle

Methylprednisolone Induces Extracellular Trap Formation and Enhances Bactericidal Effect of Canine Neutrophils

by Nicole Steffensen, Rabea Imker, Simon Lassnig, Marcus Fulde, Johanna C. Rieder and Nicole de Buhr

Int. J. Mol. Sci. 2021, 22(14), 7734; https://doi.org/10.3390/ijms22147734 - 20 Jul 2021

Cited by 9 | Viewed by 2901

Abstract

Methylprednisolone is a glucocorticoid and can negatively influence immune defense mechanisms. During bacterial infections in the dog, neutrophils infiltrate infected tissue and mediate antimicrobial effects with different mechanisms such as phagocytosis and neutrophil extracellular trap (NET) formation. Here, we investigated the influence of methylprednisolone on canine NET formation and neutrophil killing efficiency of Gram positive and Gram negative bacteria. Therefore, canine blood derived neutrophils were treated with different concentrations of methylprednisolone over time. The survival factor of Staphylococcus pseudintermedius, Streptococcus canis or Escherichia coli was determined in presence of stimulated neutrophils. Additionally, free DNA and nucleosomes as NET marker were analyzed in supernatants and neutrophils were assessed for NET formation by immunofluorescence microscopy. Methylprednisolone concentrations of 62.5 and 625 µg/mL enhanced the neutrophil killing of Gram positive bacteria, whereas no significant influence was detected for the Gram negative Escherichia coli. Interestingly, higher amounts of free DNA were detected under methylprednisolone stimulation in a concentration dependency and in the presence of Streptococcus canis and Escherichia coli. The nucleosome release by neutrophils is induced by bacterial infection and differs depending on the concentration of methylprednisolone. Furthermore, immunofluorescence microscopy analysis identified methylprednisolone at a concentration of 62.5 µg/mL as a NET inducer. In summary, methylprednisolone enhances NET-formation and time-dependent and concentration-dependent the bactericidal effect of canine neutrophils on Gram positive bacteria. Full article

(This article belongs to the Special Issue Molecular Research on Neutrophil Extracellular Trap (NET))

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16 pages, 4511 KiB

Open AccessReview

A Review of the Neutrophil Extracellular Traps (NETs) from Cow, Sheep and Goat Models

by Mulumebet Worku, Djaafar Rehrah, Hamid D. Ismail, Emmanuel Asiamah and Sarah Adjei-Fremah

Int. J. Mol. Sci. 2021, 22(15), 8046; https://doi.org/10.3390/ijms22158046 - 28 Jul 2021

Cited by 13 | Viewed by 5736

Abstract

This review provides insight into the importance of understanding NETosis in cows, sheep, and goats in light of the importance to their health, welfare and use as animal models. Neutrophils are essential to innate immunity, pathogen infection, and inflammatory diseases. The relevance of NETosis as a conserved innate immune response mechanism and the translational implications for public health are presented. Increased understanding of NETosis in ruminants will contribute to the prediction of pathologies and design of strategic interventions targeting NETs. This will help to control pathogens such as coronaviruses and inflammatory diseases such as mastitis that impact all mammals, including humans. Definition of unique attributes of NETosis in ruminants, in comparison to what has been observed in humans, has significant translational implications for one health and global food security, and thus warrants further study. Full article

(This article belongs to the Special Issue Molecular Research on Neutrophil Extracellular Trap (NET))

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