Biomedicines

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Open AccessEditorial

Neutrophils, Fast and Strong

by Galina F. Sud’ina

Biomedicines 2022, 10(8), 2040; https://doi.org/10.3390/biomedicines10082040 - 21 Aug 2022

Viewed by 1635

Abstract

The history of medicine is also the history of our understanding of the role of neutrophils in protecting our bodies [...] Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

Research

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10 pages, 7051 KiB

Open AccessArticle

Describing Characteristics and Differences of Neutrophils in Sepsis, Trauma, and Control Patients in Routinely Measured Hematology Data

by Huibert-Jan Joosse, Albert Huisman, Wouter van Solinge, Falco Hietbrink, Imo Hoefer and Saskia Haitjema

Biomedicines 2022, 10(3), 633; https://doi.org/10.3390/biomedicines10030633 - 9 Mar 2022

Cited by 3 | Viewed by 2411

Abstract

Neutrophils have an important role in the immune response. These cells can be subjected to an impaired function and a shift in population depending on disease states. In sepsis, this shift is recognized and flagged by automated hematology analyzers, including the presence of [...] Read more.

Neutrophils have an important role in the immune response. These cells can be subjected to an impaired function and a shift in population depending on disease states. In sepsis, this shift is recognized and flagged by automated hematology analyzers, including the presence of band neutrophils, while these cells, although present, appear not to be detected in trauma patients. To better understand this suspected error in flagging, we set out to distinguish neutrophil populations of these two patient groups and compared these with controls. Different data-driven methods were used compared to standard algorithms used by the software of the analyzers. Using K-means clustering, we extracted neutrophils from raw hematology analyzer datafiles, and compared characteristics of these clusters between the patient groups. We observed an increased neutrophil size for both sepsis and trauma patients, but trauma patients had a smaller increase. Trauma patients also had a high proportion of cells with relatively high nuclear segmentation, which is contradictory with the presence of band neutrophils. This, in combination with the smaller size increase, might explain the inability to flag band neutrophils in trauma. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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14 pages, 2508 KiB

Open AccessArticle

Laminin Triggers Neutrophil Extracellular Traps (NETs) and Modulates NET Release Induced by Leishmania amazonensis

by Gustavo Silva-Oliveira, Leandra Linhares-Lacerda, Thayana R. F. Mattos, Camila Sanches, Tatiana Coelho-Sampaio, Ingo Riederer and Elvira M. Saraiva

Biomedicines 2022, 10(3), 521; https://doi.org/10.3390/biomedicines10030521 - 23 Feb 2022

Cited by 6 | Viewed by 2424

Abstract

Neutrophils are recruited from the blood and transmigrate through the endothelium to reach tissues, where they are prone to respond through different mechanisms, including the release of neutrophil extracellular traps (NETs). These responses occur in close contact with proteins from the basement membrane [...] Read more.

Neutrophils are recruited from the blood and transmigrate through the endothelium to reach tissues, where they are prone to respond through different mechanisms, including the release of neutrophil extracellular traps (NETs). These responses occur in close contact with proteins from the basement membrane and extracellular matrix, where laminins are abundant. Thus, we investigated the interactions between neutrophils and different laminin (LM) isoforms and analyzed the induction of NETs. We showed that neutrophils stimulated with LM isoforms 111, 211, 332, 411, 421, and 511 released NETs. The same occurred when neutrophils interacted with polymerized LMs 111, 411, and 511. LM-induced NETs were partially inhibited by pretreatment of neutrophils with an anti-α6 integrin antibody. Furthermore, NETs triggered by laminins were dependent on elastase and peptidylarginine deiminase (PAD)-4, enzymes that participate in chromatin decondensation. We also found that LMs 411 and LM 511 potentiated the NET release promoted by promastigotes of the protozoan parasite Leishmania, and that NETs stimulated by LMs alone display leishmanicidal activity. The ability of LM to induce NET release may have potential implications for the course of inflammation or infection. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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12 pages, 1521 KiB

Open AccessArticle

SARS-CoV-2 Dysregulates Neutrophil Degranulation and Reduces Lymphocyte Counts

by Abenaya Muralidharan, Todd A. Wyatt and St Patrick Reid

Biomedicines 2022, 10(2), 382; https://doi.org/10.3390/biomedicines10020382 - 4 Feb 2022

Cited by 11 | Viewed by 4896

Abstract

SARS-CoV-2, the virus that causes COVID-19, has given rise to one of the largest pandemics, affecting millions worldwide. High neutrophil-to-lymphocyte ratios have been identified as an important correlate to poor recovery rates in severe COVID-19 patients. However, the mechanisms underlying this clinical outcome [...] Read more.

SARS-CoV-2, the virus that causes COVID-19, has given rise to one of the largest pandemics, affecting millions worldwide. High neutrophil-to-lymphocyte ratios have been identified as an important correlate to poor recovery rates in severe COVID-19 patients. However, the mechanisms underlying this clinical outcome and the reasons for its correlation to poor prognosis are unclear. Furthermore, the mechanisms involved in healthy neutrophils acquiring a SARS-CoV-2-mediated detrimental role are yet to be fully understood. In this study, we isolated circulating neutrophils from healthy donors for treatment with supernates from infected epithelial cells and direct infection with SARS-CoV-2 in vitro. Infected epithelial cells induced a dysregulated degranulation of primary granules with a decrease in myeloperoxidase (MPO), but slight increase in neutrophil elastase release. Infection of neutrophils resulted in an impairment of both MPO and elastase release, even though CD16 receptor shedding was upregulated. Importantly, SARS-CoV-2-infected neutrophils had a direct effect on peripheral blood lymphocyte counts, with decreasing numbers of CD19+ B cells, CD8+ T cells, and CD4+ T cells. Together, this study highlights the independent role of neutrophils in contributing to the aberrant immune responses observed during SARS-CoV-2 infection that may be further dysregulated in the presence of other immune cells. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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15 pages, 2581 KiB

Open AccessArticle

Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone Suppresses the Secretory Processes That Ensure the Invasion of Neutrophils into Tissues and Induce Inflammation

by Svetlana I. Galkina, Natalia V. Fedorova, Alexander L. Ksenofontov, Ekaterina A. Golenkina, Marina V. Serebryakova, Vladimir I. Stadnichuk, Ludmila A. Baratova and Galina F. Sud’ina

Biomedicines 2022, 10(2), 314; https://doi.org/10.3390/biomedicines10020314 - 28 Jan 2022

Cited by 7 | Viewed by 2695

Abstract

Integrin-dependent adhesion of neutrophils to tissue, accompanied by the development of neutrophil-induced inflammation, occurs both in the focus of infection and in the absence of infection in metabolic disorders such as reperfusion after ischemia, diabetes mellitus, or the development of pneumonia in patients [...] Read more.

Integrin-dependent adhesion of neutrophils to tissue, accompanied by the development of neutrophil-induced inflammation, occurs both in the focus of infection and in the absence of infection in metabolic disorders such as reperfusion after ischemia, diabetes mellitus, or the development of pneumonia in patients with cystic fibrosis or viral diseases. Hyaluronic acid (HA) plays an important role in the recruitment of neutrophils to tissues. 4-methylumbilliferon (4-MU), an inhibitor of HA synthesis, is used to treat inflammation, but its mechanism of action is unknown. We studied the effect of 4-MU on neutrophil adhesion and concomitant secretion using adhesion to fibronectin as a model for integrin-dependent adhesion. 4-MU reduced the spreading of neutrophils on the substrate and the concomitant secretion of granule proteins, including pro-inflammatory components. 4-MU also selectively blocked adhesion-induced release of the free amino acid hydroxylysine, a product of lysyl hydroxylase, which can influence cell invasion by modifying the extracellular matrix. Finally, 4-MU inhibited the formation of cytonemes, the extracellular membrane secretory structures containing the pro-inflammatory bactericides of the primary granules. The anti-inflammatory effect of 4-MU may be associated with the suppression of secretory processes that ensure the neutrophil invasion and initiate inflammation. We suggest that HA, due to the peculiarities of its synthesis, can promote the release of secretory carriers from the cell and 4-MU can block this process. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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15 pages, 718 KiB

Open AccessArticle

Association of Lipoproteins with Neutrophil Extracellular Traps in Patients with Abdominal Aortic Aneurysm

by Annika Brandau, Nahla Ibrahim, Johannes Klopf, Hubert Hayden, Maria Ozsvar-Kozma, Taras Afonyushkin, Sonja Bleichert, Lukas Fuchs, Viktoria Watzinger, Verena Nairz, Emely Manville, Veronika Kessler, Herbert Stangl, Wolf Eilenberg, Christoph Neumayer and Christine Brostjan

Biomedicines 2022, 10(2), 217; https://doi.org/10.3390/biomedicines10020217 - 20 Jan 2022

Cited by 10 | Viewed by 2379

Abstract

Neutrophil extracellular traps (NETs) are DNA–protein structures released by neutrophils in response to various stimuli, including oxidized, low-density lipoprotein (oxLDL). Accumulating evidence suggests a role for NETs in the pathogenesis of abdominal aortic aneurysm (AAA). In this study, we investigated the potential association [...] Read more.

Neutrophil extracellular traps (NETs) are DNA–protein structures released by neutrophils in response to various stimuli, including oxidized, low-density lipoprotein (oxLDL). Accumulating evidence suggests a role for NETs in the pathogenesis of abdominal aortic aneurysm (AAA). In this study, we investigated the potential association of lipoprotein particles and NETs in AAA in comparison to non-AAA control groups. The concentrations of neutrophil myeloperoxidase (MPO), the NET parameters citrullinated histone H3 (citH3) and circulating cell-free DNA (cfDNA), as well as of blood lipids were determined in plasma or serum of patients with AAA (n = 40), peripheral artery occlusive disease (PAD; n = 40) and healthy donors (n = 29). A sandwich ELISA detecting oxidized phosphatidylcholine in association with apolipoprotein B-100 (oxPL/apoB) was applied to measure oxidized phospholipids in circulation. The effect of lipoparticles on NET formation was tested using a DNA release assay with isolated human neutrophils. Plasma MPO, citH3 and cfDNA levels were significantly increased in AAA patients in comparison to healthy donors and PAD patients. Plasma concentrations of citH3 positively correlated with serum oxPL/apoB in AAA patients. In functional in vitro assays, the addition of oxLDL induced NET formation in pre-stimulated neutrophils. In conclusion, our data suggest a promoting role of oxLDL on NET formation in AAA patients. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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16 pages, 3670 KiB

Open AccessArticle

Galectin-9 Triggers Neutrophil-Mediated Anticancer Immunity

by Natasha Ustyanovska Avtenyuk, Ghizlane Choukrani, Emanuele Ammatuna, Toshiro Niki, Ewa Cendrowicz, Harm Jan Lourens, Gerwin Huls, Valerie R. Wiersma and Edwin Bremer

Biomedicines 2022, 10(1), 66; https://doi.org/10.3390/biomedicines10010066 - 29 Dec 2021

Cited by 11 | Viewed by 3241

Abstract

In earlier studies, galectin-9 (Gal-9) was identified as a multifaceted player in both adaptive and innate immunity. Further, Gal-9 had direct cytotoxic and tumor-selective activity towards cancer cell lines of various origins. In the current study, we identified that treatment with Gal-9 triggered [...] Read more.

In earlier studies, galectin-9 (Gal-9) was identified as a multifaceted player in both adaptive and innate immunity. Further, Gal-9 had direct cytotoxic and tumor-selective activity towards cancer cell lines of various origins. In the current study, we identified that treatment with Gal-9 triggered pronounced membrane alterations in cancer cells. Specifically, phosphatidyl serine (PS) was rapidly externalized, and the anti-phagocytic regulator, CD47, was downregulated within minutes. In line with this, treatment of mixed neutrophil/tumor cell cultures with Gal-9 triggered trogocytosis and augmented antibody-dependent cellular phagocytosis of cancer cells. Interestingly, this pro-trogocytic effect was also due to the Gal-9-mediated activation of neutrophils with upregulation of adhesion markers and mobilization of gelatinase, secretory, and specific granules. These activation events were accompanied by a decrease in cancer cell adhesion in mixed cultures of leukocytes and cancer cells. Further, prominent cytotoxicity was detected when leukocytes were mixed with pre-adhered cancer cells, which was abrogated when neutrophils were depleted. Taken together, Gal-9 treatment potently activated neutrophil-mediated anticancer immunity, resulting in the elimination of epithelial cancer cells. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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18 pages, 1851 KiB

Open AccessArticle

C3d Elicits Neutrophil Degranulation and Decreases Endothelial Cell Migration, with Implications for Patients with Alpha-1 Antitrypsin Deficiency

by Laura T. Fee, Debananda Gogoi, Michael E. O’Brien, Emer McHugh, Michelle Casey, Ciara Gough, Mark Murphy, Ann M. Hopkins, Tomás P. Carroll, Noel G. McElvaney and Emer P. Reeves

Biomedicines 2021, 9(12), 1925; https://doi.org/10.3390/biomedicines9121925 - 16 Dec 2021

Cited by 5 | Viewed by 3130

Abstract

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by increased risk for emphysema, chronic obstructive pulmonary disease (COPD), vasculitis, and wound-healing impairment. Neutrophils play a central role in the pathogenesis of AATD. Dysregulated complement activation in AATD results in increased plasma levels of C3d. [...] Read more.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by increased risk for emphysema, chronic obstructive pulmonary disease (COPD), vasculitis, and wound-healing impairment. Neutrophils play a central role in the pathogenesis of AATD. Dysregulated complement activation in AATD results in increased plasma levels of C3d. The current study investigated the impact of C3d on circulating neutrophils. Blood was collected from AATD (n = 88) or non-AATD COPD patients (n = 10) and healthy controls (HC) (n = 40). Neutrophils were challenged with C3d, and degranulation was assessed by Western blotting, ELISA, or fluorescence resonance energy transfer (FRET) substrate assays. Ex vivo, C3d levels were increased in plasma (p < 0.0001) and on neutrophil plasma membranes (p = 0.038) in AATD compared to HC. C3d binding to CR3 receptors triggered primary (p = 0.01), secondary (p = 0.004), and tertiary (p = 0.018) granule release and increased CXCL8 secretion (p = 0.02). Ex vivo plasma levels of bactericidal-permeability-increasing-protein (p = 0.02), myeloperoxidase (p < 0.0001), and lactoferrin (p < 0.0001) were significantly increased in AATD patients. In endothelial cell scratch wound assays, C3d significantly decreased cell migration (p < 0.0001), an effect potentiated by neutrophil degranulated proteins (p < 0.0001). In summary, AATD patients had increased C3d in plasma and on neutrophil membranes and, together with neutrophil-released granule enzymes, reduced endothelial cell migration and wound healing, with potential implications for AATD-related vasculitis. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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18 pages, 1632 KiB

Open AccessArticle

Simultaneous Measurement of Changes in Neutrophil Granulocyte Membrane Potential, Intracellular pH, and Cell Size by Multiparametric Flow Cytometry

by Alexander Elias Paul Stratmann, Lisa Wohlgemuth, Maike Elisabeth Erber, Stefan Bernhard, Stefan Hug, Michael Fauler, Laura Vidoni, Adam Omar Khalaf Mohamed, Bertram Dietrich Thomaß, Frederik Münnich, Laura Stukan, Karl Josef Föhr, Marco Mannes, Markus Stefan Huber-Lang and David Alexander Christian Messerer

Biomedicines 2021, 9(11), 1504; https://doi.org/10.3390/biomedicines9111504 - 20 Oct 2021

Cited by 3 | Viewed by 4294

Abstract

Neutrophils provide rapid and efficient defense mechanisms against invading pathogens. Upon stimulation with proinflammatory mediators, including complement factors and bacterial peptides, neutrophils respond with changes in their membrane potential, intracellular pH, and cellular size. This study provides an approach to quantify these important [...] Read more.

Neutrophils provide rapid and efficient defense mechanisms against invading pathogens. Upon stimulation with proinflammatory mediators, including complement factors and bacterial peptides, neutrophils respond with changes in their membrane potential, intracellular pH, and cellular size. This study provides an approach to quantify these important changes simultaneously using multiparametric flow cytometry, thereby revealing a typical sequence of neutrophil activation consisting of depolarization, alkalization, and increase in cellular size. Additionally, the time resolution of the flow cytometric measurement is improved in order to allow changes that occur within seconds to be monitored, and thus to enhance the kinetic analysis of the neutrophil response. The method is appropriate for the reliable semiquantitative detection of small variations with respect to an increase, no change, and decrease in those parameters as demonstrated by the screening of various proinflammatory mediators. As a translational outlook, the findings are put into context in inflammatory conditions in vitro as well as in a clinically relevant whole blood model of endotoxemia. Taken together, the multiparametric analysis of neutrophil responsiveness regarding depolarization, alkalization, and changes in cellular size may contribute to a better understanding of neutrophils in health and disease, thus potentially yielding innovative mechanistic insights and possible novel diagnostic and/or prognostic approaches. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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12 pages, 844 KiB

Open AccessArticle

Lenalidomide and Pomalidomide Improve Function and Induce FcγRI/CD64 in Multiple Myeloma Neutrophils

by Alessandra Romano, Nunziatina Laura Parrinello, Marina Parisi, Vittorio Del Fabro, Angelo Curtopelle, Salvatore Leotta, Concetta Conticello and Francesco Di Raimondo

Biomedicines 2021, 9(10), 1455; https://doi.org/10.3390/biomedicines9101455 - 13 Oct 2021

Cited by 2 | Viewed by 2497

Abstract

Background Myeloid dysfunction is an emerging hallmark of microenvironment changes occurring in multiple myeloma (MM). Our previous work showed that FcγRI/CD64 overexpression in neutrophils of newly diagnosed MM patients is associated to inferior outcomes, reduced oxidative bursts and phagocytosis, with an increased risk [...] Read more.

Background Myeloid dysfunction is an emerging hallmark of microenvironment changes occurring in multiple myeloma (MM). Our previous work showed that FcγRI/CD64 overexpression in neutrophils of newly diagnosed MM patients is associated to inferior outcomes, reduced oxidative bursts and phagocytosis, with an increased risk of bacterial infections. Pomalidomide is a novel immune-modulatory drug approved for relapsed/refractory patients (RRMM), with drug-related neutropenia as major limitation to treatment. Patients and methods Herein, we describe a prospective analysis of 51 consecutive RRMM patients treated with pomalidomide and dexamethasone (PomDex) from March 2015 through December 2016, associated with secondary prophylaxis with filgrastim (G-CSF) in case of neutrophil count <1500 cells/μL. Neutrophil function was investigated by flow cytometry, including the phagocytosis, oxidative bursts, and median fluorescence intensity of FcγRI-CD64. Controls included a group of newly diagnosed symptomatic MM (NDMM), asymptomatic (smoldering myeloma, MGUS) and healthy subjects referred to our Center in the same time-frame. Results Compared to controls, RRMM neutrophils had higher expression of FcγRI/CD64 and lower phagocytic activity and oxidative bursts. We maintained median leukocyte counts higher than 3.5 × 10⁹/L for 6 cycles, and median neutrophil counts higher than 1.5 × 10⁹/L, with only 6 (11%) patients developing grade 3–4 infections, without pomalidomide dose reduction. After 4 cycles of PomDex, FcγRI/CD64 was further increased in neutrophils, and phagocytic activity and oxidative bursts recovered independently from filgrastim exposure and the quality of hematological responses. Similarly, in NDMM patients, lenalidomide but not bortezomib upregulated FcγRI/CD64 expression, improving phagocytic activity and oxidative bursta as tested in vitro. Conclusions Our combined biological and clinical data provide new information on the ability of pomalidomide and lenalidomide to modulate the functional activity of neutrophils, despite their chronic activation due to FcγRI/CD64 overexpression. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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14 pages, 2458 KiB

Open AccessArticle

Prolyl-Isomerase Pin1 Controls Key fMLP-Induced Neutrophil Functions

by Samia Bedouhene, Min Liu, Nassima Senani, Tarek Boussetta, Coralie Pintard, Pham My-Chan Dang and Jamel El-Benna

Biomedicines 2021, 9(9), 1130; https://doi.org/10.3390/biomedicines9091130 - 1 Sep 2021

Cited by 7 | Viewed by 2600

Abstract

Neutrophils are key cells of the innate immune and inflammatory responses. They are the first blood cells to migrate to the infection site where they release high amounts of reactive oxygen species (ROS) and several peptides and enzymes required for microbial killing. However, [...] Read more.

Neutrophils are key cells of the innate immune and inflammatory responses. They are the first blood cells to migrate to the infection site where they release high amounts of reactive oxygen species (ROS) and several peptides and enzymes required for microbial killing. However, excessive neutrophil activation can induce tissue injury participating in inflammation, thus the characterization of the enzymes involved in neutrophil activation could help to identify new pharmacological targets to treat inflammation. The prolyl-isomerase Pin1 is a ubiquitous enzyme involved in several functions, however, its role in neutrophil functions is less known. In this study, we show that the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP or fMLF), a G-protein coupled receptor (GPCR) agonist-induced Pin1 activation in human neutrophils. PiB and juglone, two Pin1 inhibitors inhibited Pin1 activity in neutrophils and consequently inhibited fMLP-induced chemotaxis and -degranulation of azurophil and specific granules as measured by myeloperoxidase and neutrophil gelatinase-associated lipocalin (NGAL) release respectively. We also showed that PiB inhibited TNFα + fMLP-induced superoxide production, confirming the effect of juglone. These data show that inhibitors of Pin1 impaired key pro-inflammatory neutrophil functions elicited by GPCR activation and suggest that Pin1 could control neutrophil inflammatory functions. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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Review

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15 pages, 815 KiB

Open AccessReview

The Involvement of Neutrophils in the Pathophysiology and Treatment of Osteoarthritis

by Shelby Chaney, Rosemary Vergara, Zeena Qiryaqoz, Kelsey Suggs and Adil Akkouch

Biomedicines 2022, 10(7), 1604; https://doi.org/10.3390/biomedicines10071604 - 6 Jul 2022

Cited by 36 | Viewed by 4398

Abstract

Osteoarthritis (OA) is a chronic disability that significantly impairs quality of life. OA is one of the most prevalent joint pathologies in the world, characterized by joint pain and stiffness due to the degeneration of articular cartilage and the remodeling of subchondral bone. [...] Read more.

Osteoarthritis (OA) is a chronic disability that significantly impairs quality of life. OA is one of the most prevalent joint pathologies in the world, characterized by joint pain and stiffness due to the degeneration of articular cartilage and the remodeling of subchondral bone. OA pathogenesis is unique in that it involves simultaneous reparative and degradative mechanisms. Low-grade inflammation as opposed to high-grade allows for this coexistence. Previously, macrophages and T cells have been identified as playing major roles in the inflammation and destruction of OA joints, but recent studies have demonstrated that neutrophils also contribute to the pathogenesis. Neutrophils are the first immune cells to enter the synovium after joint injury, and neutrophilic activity is indispensably a requisite for the progression of OA. Neutrophils act through multiple mechanisms including tissue degeneration via neutrophil elastase (NE), osteophyte development, and the release of inflammatory cytokines and chemokines. As the actions of neutrophils in OA are discovered, the potential for novel therapeutic targets as well as diagnostic methods are revealed. The use of chondrogenic progenitor cells (CPCs), microRNAs, and exosomes are among the newest therapeutic advances in OA treatment, and this review reveals how they can be used to mitigate destructive neutrophil activity. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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24 pages, 1555 KiB

Open AccessReview

Molecular Basis for Paradoxical Activities of Polymorphonuclear Neutrophils in Inflammation/Anti-Inflammation, Bactericide/Autoimmunity, Pro-Cancer/Anticancer, and Antiviral Infection/SARS-CoV-II-Induced Immunothrombotic Dysregulation

by Tsai-Hung Wu, Song-Chou Hsieh, Tsu-Hao Li, Cheng-Hsun Lu, Hsien-Tzung Liao, Chieh-Yu Shen, Ko-Jen Li, Cheng-Han Wu, Yu-Min Kuo, Chang-Youh Tsai and Chia-Li Yu

Biomedicines 2022, 10(4), 773; https://doi.org/10.3390/biomedicines10040773 - 25 Mar 2022

Cited by 5 | Viewed by 4716

Abstract

Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cells in the circulation. These cells act as the fast and powerful defenders against environmental pathogenic microbes to protect the body. In addition, these innate inflammatory cells can produce a number of cytokines/chemokines/growth factors [...] Read more.

Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cells in the circulation. These cells act as the fast and powerful defenders against environmental pathogenic microbes to protect the body. In addition, these innate inflammatory cells can produce a number of cytokines/chemokines/growth factors for actively participating in the immune network and immune homeostasis. Many novel biological functions including mitogen-induced cell-mediated cytotoxicity (MICC) and antibody-dependent cell-mediated cytotoxicity (ADCC), exocytosis of microvesicles (ectosomes and exosomes), trogocytosis (plasma membrane exchange) and release of neutrophil extracellular traps (NETs) have been successively discovered. Furthermore, recent investigations unveiled that PMNs act as a double-edged sword to exhibit paradoxical activities on pro-inflammation/anti-inflammation, antibacteria/autoimmunity, pro-cancer/anticancer, antiviral infection/COVID-19-induced immunothrombotic dysregulation. The NETs released from PMNs are believed to play a pivotal role in these paradoxical activities, especially in the cytokine storm and immunothrombotic dysregulation in the recent SARS-CoV-2 pandemic. In this review, we would like to discuss in detail the molecular basis for these strange activities of PMNs. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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18 pages, 1152 KiB

Open AccessReview

Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment

by María Amparo Blanch-Ruiz, Raquel Ortega-Luna, Guillermo Gómez-García, Maria Ángeles Martínez-Cuesta and Ángeles Álvarez

Biomedicines 2022, 10(1), 31; https://doi.org/10.3390/biomedicines10010031 - 23 Dec 2021

Cited by 17 | Viewed by 4283

Abstract

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has resulted in a pandemic with over 270 million confirmed cases and 5.3 million deaths worldwide. In some cases, the infection leads to acute respiratory distress syndrome (ARDS), which is triggered by a cytokine storm [...] Read more.

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has resulted in a pandemic with over 270 million confirmed cases and 5.3 million deaths worldwide. In some cases, the infection leads to acute respiratory distress syndrome (ARDS), which is triggered by a cytokine storm and multiple organ failure. Clinical hematological, biochemical, coagulation, and inflammatory markers, such as interleukins, are associated with COVID-19 disease progression. In this regard, neutrophilia, neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-albumin ratio (NAR), have emerged as promising biomarkers of disease severity and progression. In the pathophysiology of ARDS, the inflammatory environment induces neutrophil influx and activation in the lungs, promoting the release of cytokines, proteases, reactive oxygen species (ROS), and, eventually, neutrophil extracellular traps (NETs). NETs components, such as DNA, histones, myeloperoxidase, and elastase, may exert cytotoxic activity and alveolar damage. Thus, NETs have also been described as potential biomarkers of COVID-19 prognosis. Several studies have demonstrated that NETs are induced in COVID-19 patients, and that the highest levels of NETs are found in critical ones, therefore highlighting a correlation between NETs and severity of the disease. Knowledge of NETs signaling pathways, and the targeting of points of NETs release, could help to develop an effective treatment for COVID-19, and specifically for severe cases, which would help to manage the pandemic. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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13 pages, 4003 KiB

Open AccessReview

Neutrophil Extracellular Traps in Skin Diseases

by Youichi Ogawa, Yoshinori Muto, Manao Kinoshita, Shinji Shimada and Tatsuyoshi Kawamura

Biomedicines 2021, 9(12), 1888; https://doi.org/10.3390/biomedicines9121888 - 12 Dec 2021

Cited by 17 | Viewed by 8368

Abstract

Neutrophils are the primary innate immune cells, and serve as sentinels for invading pathogens. To this end, neutrophils exert their effector functions via phagocytosis, degranulation, reactive oxygen species generation, and neutrophil extracellular trap (NET) release. Pathogens and pathogen-derived components trigger NET formation, leading [...] Read more.

Neutrophils are the primary innate immune cells, and serve as sentinels for invading pathogens. To this end, neutrophils exert their effector functions via phagocytosis, degranulation, reactive oxygen species generation, and neutrophil extracellular trap (NET) release. Pathogens and pathogen-derived components trigger NET formation, leading to the clearance of pathogens. However, NET formation is also induced by non-related pathogen proteins, such as cytokines and immune complexes. In this regard, NET formation can be induced under both non-sterile and sterile conditions. NETs are enriched by components with potent cytotoxic and inflammatory properties, thereby occasionally damaging tissues and cells and dysregulating immune homeostasis. Research has uncovered the involvement of NETs in the pathogenesis of several connective tissue diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and ANCA-associated vasculitis. In dermatology, several skin diseases clinically develop local or systemic sterile pustules and abscesses. The involvement of neutrophils and subsequent NET formation has recently been elucidated in these skin diseases. Therefore, this review highlights the NETs in these neutrophil-associated diseases. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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28 pages, 1123 KiB

Open AccessReview

Neutrophils as Regulators and Biomarkers of Cardiovascular Inflammation in the Context of Abdominal Aortic Aneurysms

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

Biomedicines 2021, 9(9), 1236; https://doi.org/10.3390/biomedicines9091236 - 16 Sep 2021

Cited by 26 | Viewed by 5194

Abstract

Neutrophils represent up to 70% of circulating leukocytes in healthy humans and combat infection mostly by phagocytosis, degranulation and NETosis. It has been reported that neutrophils are centrally involved in abdominal aortic aneurysm (AAA) pathogenesis. The natural course of AAA is growth and [...] Read more.

Neutrophils represent up to 70% of circulating leukocytes in healthy humans and combat infection mostly by phagocytosis, degranulation and NETosis. It has been reported that neutrophils are centrally involved in abdominal aortic aneurysm (AAA) pathogenesis. The natural course of AAA is growth and rupture, if left undiagnosed or untreated. The rupture of AAA has a very high mortality and is currently among the leading causes of death worldwide. The use of noninvasive cardiovascular imaging techniques for patient screening, surveillance and postoperative follow-up is well established and recommended by the current guidelines. Neutrophil-derived biomarkers may offer clinical value to the monitoring and prognosis of AAA patients, allowing for potential early therapeutic intervention. Numerous promising biomarkers have been studied. In this review, we discuss neutrophils and neutrophil-derived molecules as regulators and biomarkers of AAA, and our aim was to specifically highlight diagnostic and prognostic markers. Neutrophil-derived biomarkers may potentially, in the future, assist in determining AAA presence, predict size, expansion rate, rupture risk, and postoperative outcome once validated in highly warranted future prospective clinical studies. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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