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

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 64537

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Prof. Dr. Yoshiro Kobayashi

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Division of Molecular Medicine, Department of Biomolecular Science, Faculty of Science, Toho University, Tokyo, Japan
Interests: apoptosis; inflammation; immunology of infectious diseases; innate immunity; cytokines; monocytes; neutrophils; macrophage biology; chemokines; phagocytosis; nitric oxide (NO)
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Dear Colleagues,

Research on neutrophil biology has been expanding recently. NETs formation, NETosis, and their role in diseases or their models is one such research area. Another area involves research on the fate of neutrophils during resolution, cell death, phagocytosis of dead neutrophils, and/or reverse migration. Upon inflammation, neutrophils are recruited to the site from the reservoirs by means of not only chemokines but also other mediators. Subsets of neutrophils have also been identified in various settings. Various hereditary diseases in mice and humans have also been described, unveiling the hitherto unrecognized regulatory mechanisms of neutrophil development. There may be unknown, perhaps not fully characterized, phenomena in neutrophil biology. Taken together, I would like to urge researchers who have engaged in such research areas actively to provide along with their results, their thoughts and the current status of their research area, so that readers can enjoy reading innovative papers and that help predict the future directions of neutrophil biology.

Prof. Dr. Yoshiro Kobayashi
Guest Editor

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Keywords

NETs
Recruitment
Resolution
Cell death
Phagocytosis
Reverse migration
Neutrophil subsets
Hereditary diseases

Related Special Issue

Current Trends of Neutrophil Biology 2.0 in International Journal of Molecular Sciences (8 articles)

Published Papers (11 papers)

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Editorial

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3 pages, 162 KiB

Open AccessEditorial

Current Trends of Neutrophil Biology

by Yoshiro Kobayashi

Int. J. Mol. Sci. 2020, 21(23), 9071; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239071 - 28 Nov 2020

Cited by 1 | Viewed by 1348

Abstract

Neutrophils are short-lived and terminally differentiated cells, and therefore, have been considered as effector cells to phagocytose pathogens and kill them or damage tissues [...] Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

Research

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18 pages, 1972 KiB

Open AccessArticle

Characterization of the Impact of Oncolytic Vesicular Stomatitis Virus on the Trafficking, Phenotype, and Antigen Presentation Potential of Neutrophils and Their Ability to Acquire a Non-Structural Viral Protein

by Ashley A. Stegelmeier, Lily Chan, Yeganeh Mehrani, James J. Petrik, Sarah K. Wootton, Byram Bridle and Khalil Karimi

Int. J. Mol. Sci. 2020, 21(17), 6347; https://doi.org/10.3390/ijms21176347 - 01 Sep 2020

Cited by 11 | Viewed by 2799

Abstract

Neutrophils are innate leukocytes that mount a rapid response to invading pathogens and sites of inflammation. Although neutrophils were traditionally considered responders to bacterial infections, recent advances have demonstrated that they are interconnected with both viral infections and cancers. One promising treatment strategy for cancers is to administer an oncolytic virus to activate the immune system and directly lyse cancerous cells. A detailed characterization of how the innate immune system responds to a viral-based therapy is paramount in identifying its systemic effects. This study analyzed how administering the rhabdovirus vesicular stomatitis virus (VSV) intravenously at 1 × 10⁹ PFU acutely influenced neutrophil populations. Bone marrow, blood, lungs, and spleen were acquired three- and 24-h after administration of VSV for analysis of neutrophils by flow cytometry. Infection with VSV caused neutrophils to rapidly egress from the bone marrow and accumulate in the lungs. A dramatic increase in immature neutrophils was observed in the lungs, as was an increase in the antigen presentation potential of these cells within the spleen. Furthermore, the potential for neutrophils to acquire viral transgene-encoded proteins was monitored using a variant of VSV that expressed enhanced green fluorescent protein (GFP). If an in vitro population of splenocytes were exposed to αCD3 and αCD28, a substantial proportion of the neutrophils would become GFP-positive. This suggested that the neutrophils could either acquire more virus-encoded antigens from infected splenocytes or were being directly infected. Five different dosing regimens were tested in mice, and it was determined that a single dose of VSV or two doses of VSV administered at a 24-h interval, resulted in a substantial proportion of neutrophils in the bone marrow becoming GFP-positive. This correlated with a decrease in the number of splenic neutrophils. Two doses administered at intervals longer than 24-h did not have these effects, suggesting that neutrophils became resistant to antigen uptake or direct infection with VSV beyond 24-h of activation. These findings implicated neutrophils as major contributors to oncolytic rhabdoviral therapies. They also provide several clear future directions for research and suggest that neutrophils should be carefully monitored during the development of all oncolytic virus-based treatment regimens. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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12 pages, 2133 KiB

Open AccessArticle

Overexpression of ATG5 Gene Makes Granulocyte-Like HL-60 Susceptible to Release Reactive Oxygen Species

by Agnieszka Mroczek, Adrianna Cieloch, Aneta Manda-Handzlik, Weronika Kuźmicka, Angelika Muchowicz and Małgorzata Wachowska

Int. J. Mol. Sci. 2020, 21(15), 5194; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155194 - 22 Jul 2020

Cited by 5 | Viewed by 3540

Abstract

Neutrophils represent the first line of defense against pathogens using various strategies, such as phagocytosis, production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) formation. Recently, an autophagy-independent role of autophagy related (ATG) gene 5 in immune cells, including neutrophils, was emphasized. Our aim was to investigate the role of ATG5 protein in neutrophils’ antimicrobial functions, proliferation and apoptosis. To this end, we used genetically modified human promyelocytic leukemia (HL-60) cells overexpressing ATG5, differentiated toward granulocyte-like cells with all-trans retinoic acid (ATRA) and dimethylformamide. The level of differentiation, phagocytosis, proliferation and apoptosis were determined by flow cytometry. ROS production and NETs release was assessed by fluorometry and fluorescent microscopy. ATG5 gene expression was evaluated by real-time PCR, whereas the protein level of ATG5 and LC3-II was determined by Western blot. We did not observe the induction of autophagy in differentiated HL-60 cells overexpressing ATG5. The increased expression of ATG5 affects the differentiation of HL-60 cells with ATRA, ROS production and phagocytosis. However, we did not detect changes in NETs release. Moreover, ATG5 protects differentiated HL-60 cells from apoptosis but does not cause changes in proliferation rate. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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17 pages, 7424 KiB

Open AccessArticle

Nintedanib Reduces Neutrophil Chemotaxis via Activating GRK2 in Bleomycin-Induced Pulmonary Fibrosis

by Wei-Chih Chen, Nien-Jung Chen, Hsin-Pai Chen, Wen-Kuang Yu, Vincent Yi-Fong Su, Hao Chen, Huai-Hsuan Wu and Kuang-Yao Yang

Int. J. Mol. Sci. 2020, 21(13), 4735; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134735 - 02 Jul 2020

Cited by 23 | Viewed by 4710

Abstract

Neutrophils are involved in the alveolitis of idiopathic pulmonary fibrosis (IPF). However, their pathogenic mechanisms are still poorly understood. Nintedanib has antifibrotic and anti-inflammatory activity in IPF. This study aimed to investigate the regulatory mechanism of nintedanib on neutrophil chemotaxis in bleomycin (BLM)-induced pulmonary fibrosis. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h after a bleomycin intratracheal injection (1.5 U/kg). Lung histopathological findings, the expression of cytokines, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed. The effect of nintedanib was also investigated in a mouse model with adoptive neutrophil transfer in vivo. Nintedanib significantly decreased the histopathological changes and neutrophil recruitment in BLM-induced pulmonary fibrosis. Nintedanib mediated a downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and very late antigen 4 (VLA-4) expression, as well as an upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in BLM-induced pulmonary fibrosis. Nintedanib also decreased the activation of endothelial cells by the decreased expression of vascular cell adhesion molecule 1 (VCAM-1). The effect of nintedanib on regulating neutrophil chemotaxis was also confirmed by a mouse model with adoptive neutrophil transfer in vivo. In conclusion, nintedanib reduces neutrophil chemotaxis and endothelial cell activation to regulate the severity of BLM-induced pulmonary fibrosis. These effects are associated with an enhancement of GRK2 activity and a reduction in CXCR2 and VLA-4 expression on neutrophils and a decrease in VCAM-1 expression on endothelial cells. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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15 pages, 2635 KiB

Open AccessArticle

In Vivo Transmigrated Human Neutrophils Are Highly Primed for Intracellular Radical Production Induced by Monosodium Urate Crystals

by Lisa Davidsson, Agnes Dahlstrand Rudin, Felix Peter Sanchez Klose, Alicia Buck, Lena Björkman, Karin Christenson and Johan Bylund

Int. J. Mol. Sci. 2020, 21(11), 3750; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113750 - 26 May 2020

Cited by 12 | Viewed by 2672

Abstract

Gout is an inflammatory disease caused by monosodium urate (MSU) crystals. The role of neutrophils in gout is less clear, although several studies have shown neutrophil extracellular trap (NET) formation in acutely inflamed joints of gout patients. MSU crystals are known to induce the production of reactive oxygen species (ROS) and NET formation in neutrophils isolated from blood, but there is inconclusive knowledge on the localization of ROS production as well as whether the ROS are required for NET formation. In this report we demonstrate that MSU crystals activate human neutrophils to produce ROS exclusively in intracellular compartments. Additionally, in vivo transmigrated neutrophils derived from experimental skin chambers displayed markedly increased ROS production as compared to resting blood neutrophils. We also confirmed that MSU stimulation potently induced NET formation, but this response was not primed in in vivo transmigrated neutrophils. In line with this we found that MSU-triggered NET formation was independent of ROS production and proceeded normally in neutrophils from patients with dysfunctional respiratory burst (chronic granulomatous disease (CGD) and complete myeloperoxidase (MPO) deficiency). Our data indicate that in vivo transmigrated neutrophils are markedly primed for oxidative responses to MSU crystals and that MSU triggered NET formation is independent of ROS production. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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13 pages, 5658 KiB

Open AccessArticle

Mesenchymal Stem Cell-Conditioned Medium Induces Neutrophil Apoptosis Associated with Inhibition of the NF-κB Pathway in Endotoxin-Induced Acute Lung Injury

by Vincent Yi-Fong Su, Chi-Shiuan Lin, Shih-Chieh Hung and Kuang-Yao Yang

Int. J. Mol. Sci. 2019, 20(9), 2208; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092208 - 05 May 2019

Cited by 82 | Viewed by 6225

Abstract

The immunomodulatory effects of mesenchymal stem cells (MSCs) are established. However, the effects of MSCs on neutrophil survival in acute lung injury (ALI) remain unclear. The goal of this study was to investigate the effect of an MSC-conditioned medium (MSC-CM) on neutrophil apoptosis in endotoxin-induced ALI. In this study, an MSC-CM was delivered via tail vein injection to wild-type male C57BL/6 mice 4 h after an intratracheal injection of lipopolysaccharide (LPS). Twenty-four hours later, bronchoalveolar lavage fluid (BALF) and lung tissue were collected to perform histology, immunohistochemistry, apoptosis assay of neutrophil, enzyme-linked immunosorbent assays, and an electrophoretic mobility shift assay. Human neutrophils were also collected from patients with sepsis-induced acute respiratory distress syndrome (ARDS). Human neutrophils were treated in vitro with LPS, with or without subsequent MSC-CM co-treatment, and were then analyzed. Administration of the MSC-CM resulted in a significant attenuation of histopathological changes, the levels of interleukin-6 and macrophage inflammatory protein 2, and neutrophil accumulation in mouse lung tissues of LPS-induced ALI. Additionally, MSC-CM therapy enhanced the apoptosis of BALF neutrophils and reduced the expression of the anti-apoptotic molecules, Bcl-xL and Mcl-1, both in vivo and in vitro experiments. Furthermore, phosphorylated and total levels of nuclear factor (NF)-κB p65 were reduced in lung tissues from LPS + MSC-CM mice. Human MSC-CM also reduced the activity levels of NF-κB and matrix metalloproteinase-9 in the human neutrophils from ARDS patients. Thus, the results of this study suggest that the MSC-CM attenuated LPS-induced ALI by inducing neutrophil apoptosis, associated with inhibition of the NF-κB pathway. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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Review

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25 pages, 1186 KiB

Open AccessReview

Neutrophils: Underestimated Players in the Pathogenesis of Multiple Sclerosis (MS)

by Mirre De Bondt, Niels Hellings, Ghislain Opdenakker and Sofie Struyf

Int. J. Mol. Sci. 2020, 21(12), 4558; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124558 - 26 Jun 2020

Cited by 53 | Viewed by 8045

Abstract

Neutrophils are the most abundant circulating and first-responding innate myeloid cells and have so far been underestimated in the context of multiple sclerosis (MS). MS is the most frequent, immune-mediated, inflammatory disease of the central nervous system. MS is treatable but not curable and its cause(s) and pathogenesis remain elusive. The involvement of neutrophils in MS pathogenesis has been suggested by the use of preclinical animal disease models, as well as on the basis of patient sample analysis. In this review, we provide an overview of the possible mechanisms and functions by which neutrophils may contribute to the development and pathology of MS. Neutrophils display a broad variety of effector functions enabling disease pathogenesis, including (1) the release of inflammatory mediators and enzymes, such as interleukin-1β, myeloperoxidase and various proteinases, (2) destruction and phagocytosis of myelin (as debris), (3) release of neutrophil extracellular traps, (4) production of reactive oxygen species, (5) breakdown of the blood–brain barrier and (6) generation and presentation of autoantigens. An important question relates to the issue of whether neutrophils exhibit a predominantly proinflammatory function or are also implicated in the resolution of chronic inflammatory responses in MS. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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37 pages, 11272 KiB

Open AccessReview

What Is the Evolutionary Fingerprint in Neutrophil Granulocytes?

by Leonie Fingerhut, Gaby Dolz and Nicole de Buhr

Int. J. Mol. Sci. 2020, 21(12), 4523; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124523 - 25 Jun 2020

Cited by 44 | Viewed by 14582

Abstract

Over the years of evolution, thousands of different animal species have evolved. All these species require an immune system to defend themselves against invading pathogens. Nevertheless, the immune systems of different species are obviously counteracting against the same pathogen with different efficiency. Therefore, the question arises if the process that was leading to the clades of vertebrates in the animal kingdom—namely mammals, birds, amphibians, reptiles, and fish—was also leading to different functions of immune cells. One cell type of the innate immune system that is transmigrating as first line of defense in infected tissue and counteracts against pathogens is the neutrophil granulocyte. During the host–pathogen interaction they can undergo phagocytosis, apoptosis, degranulation, and form neutrophil extracellular traps (NETs). In this review, we summarize a wide spectrum of information about neutrophils in humans and animals, with a focus on vertebrates. Special attention is kept on the development, morphology, composition, and functions of these cells, but also on dysfunctions and options for cell culture or storage. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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21 pages, 1169 KiB

Open AccessReview

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

by Vincent D. Giacalone, Camilla Margaroli, Marcus A. Mall and Rabindra Tirouvanziam

Int. J. Mol. Sci. 2020, 21(3), 851; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030851 - 28 Jan 2020

Cited by 56 | Viewed by 8860

Abstract

Neutrophils have a prominent role in all human immune responses against any type of pathogen or stimulus. The lungs are a major neutrophil reservoir and neutrophilic inflammation is a primary response to both infectious and non-infectious challenges. While neutrophils are well known for their essential role in clearance of bacteria, they are also equipped with specific mechanisms to counter viruses and fungi. When these defense mechanisms become aberrantly activated in the absence of infection, this commonly results in debilitating chronic lung inflammation. Clearance of bacteria by phagocytosis is the hallmark role of neutrophils and has been studied extensively. New studies on neutrophil biology have revealed that this leukocyte subset is highly adaptable and fulfills diverse roles. Of special interest is how these adaptations can impact the outcome of an immune response in the lungs due to their potent capacity for clearing infection and causing damage to host tissue. The adaptability of neutrophils and their propensity to influence the outcome of immune responses implicates them as a much-needed target of future immunomodulatory therapies. This review highlights the recent advances elucidating the mechanisms of neutrophilic inflammation, with a focus on the lung environment due to the immense and growing public health burden of chronic lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), and acute lung inflammatory diseases such as transfusion-related acute lung injury (TRALI). Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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22 pages, 39692 KiB

Open AccessReview

Cytonemes Versus Neutrophil Extracellular Traps in the Fight of Neutrophils with Microbes

by Svetlana I. Galkina, Natalia V. Fedorova, Ekaterina A. Golenkina, Vladimir I. Stadnichuk and Galina F. Sud’ina

Int. J. Mol. Sci. 2020, 21(2), 586; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020586 - 16 Jan 2020

Cited by 15 | Viewed by 7622

Abstract

Neutrophils can phagocytose microorganisms and destroy them intracellularly using special bactericides located in intracellular granules. Recent evidence suggests that neutrophils can catch and kill pathogens extracellularly using the same bactericidal agents. For this, live neutrophils create a cytoneme network, and dead neutrophils provide chromatin and proteins to form neutrophil extracellular traps (NETs). Cytonemes are filamentous tubulovesicular secretory protrusions of living neutrophils with intact nuclei. Granular bactericides are localized in membrane vesicles and tubules of which cytonemes are composed. NETs are strands of decondensed DNA associated with histones released by died neutrophils. In NETs, bactericidal neutrophilic agents are adsorbed onto DNA strands and are not covered with a membrane. Cytonemes and NETs occupy different places in protecting the body against infections. Cytonemes can develop within a few minutes at the site of infection through the action of nitric oxide or actin-depolymerizing alkaloids of invading microbes. The formation of NET in vitro occurs due to chromatin decondensation resulting from prolonged activation of neutrophils with PMA (phorbol 12-myristate 13-acetate) or other stimuli, or in vivo due to citrullination of histones with peptidylarginine deiminase 4. In addition to antibacterial activity, cytonemes are involved in cell adhesion and communications. NETs play a role in autoimmunity and thrombosis. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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17 pages, 1656 KiB

Open AccessReview

DGKα in Neutrophil Biology and Its Implications for Respiratory Diseases

by Gianluca Baldanzi and Mario Malerba

Int. J. Mol. Sci. 2019, 20(22), 5673; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225673 - 13 Nov 2019

Cited by 5 | Viewed by 3040

Abstract

Diacylglycerol kinases (DGKs) play a key role in phosphoinositide signaling by removing diacylglycerol and generating phosphatidic acid. Besides the well-documented role of DGKα and DGKζ as negative regulators of lymphocyte responses, a robust body of literature points to those enzymes, and specifically DGKα, as crucial regulators of leukocyte function. Upon neutrophil stimulation, DGKα activation is necessary for migration and a productive response. The role of DGKα in neutrophils is evidenced by its aberrant behavior in juvenile periodontitis patients, which express an inactive DGKα transcript. Together with in vitro experiments, this suggests that DGKs may represent potential therapeutic targets for disorders where inflammation, and neutrophils in particular, plays a major role. In this paper we focus on obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD), but also rare genetic diseases such as alpha-1-antitrypsin deficiency. Indeed, the biological role of DGKα is understudied outside the T lymphocyte field. The recent wave of research aiming to develop novel and specific inhibitors as well as KO mice will allow a better understanding of DGK’s role in neutrophilic inflammation. Better knowledge and pharmacologic tools may also allow DGK to move from the laboratory bench to clinical trials. Full article

(This article belongs to the Special Issue Current Trends of Neutrophil Biology)

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