Emerging Roles of Neutrophil in Inflammation and Immunity

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cellular Immunology".

Viewed by 43643

Editors


E-Mail Website
Collection Editor
1. Division of Infectious Disease and Immunology, CHU de Quebec Research Center, Quebec, QC, Canada
2. Centre ARThrite, Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Quebec, QC, Canada
Interests: rheumatic diseases; inflammation; neutrophils; signaling; chemokines

E-Mail Website
Collection Editor
1. Division of Infectious Disease and Immunology, CHU de Quebec Research Center, Quebec, QC, Canada
2. Centre ARThrite, Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Quebec, QC, Canada
Interests: autoimmunity; inflammation; immunometabolism; metabolic reprogramming

E-Mail Website
Collection Editor
1. Department of Medicine, Laval University, Quebec, Canada
2. Division of Infectious Disease and Immunology, CHU de Quebec Research Center, Quebec, QC, Canada
Interests: arthritis; autoimmunity; resolution of inflammation; neutrophil plasticity

Topical Collection Information

Dear Colleagues,

PMNs are indispensable cells in the innate immune system. They are produced in the bone marrow and released into the circulation. Blood neutrophils are a complex population of polymorphonuclear leukocytes that are recruited in response to inflammatory mediators released by an inflamed tissue. Neutrophil functions are associated with their physiological status. Neutrophil heterogeneity has been highlighted in pathological conditions including infections, inflammation, autoimmunity and cancers. The ability of neutrophils to change their phenotypes, acquire new functions and adapt to the microenvironment in which they are attracted includes antigen presentation and a variety of anti-inflammatory and pro-revolving properties. Furthermore, energy production in PMNs depends on glycolysis and less on the oxidative phosphorylation pathway because they have only a few mitochondria. Though glycolysis supports the enhanced energy demand of activated PMNs, the cells must rewire their metabolism to adapt the microenvironment and sustain their transition from a pro-inflammatory towards a pro-resolving phenotype.

In this Topical Collection of Cells, we invite you to contribute original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Emerging Roles of Neutrophil in Inflammation and Immunity”. Articles describing neutrophil heterogeneity in health and diseases, immunometabolism, acquisition of new functions, or general aspects of neutrophil physiology are highly welcome. Relevant topics include but are not limited to:

Prof. Dr. Sylvain G. Bourgoin
Prof. Dr. Martin Pelletier
Prof. Dr. Patrice E. Poubelle
Collection Editors

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Keywords

  • neutrophil heterogeneity
  • plasticity
  • reprogramming
  • low density neutrophils
  • functions
  • signaling
  • • Autoimmunity
  • • Inflammation
  • • Resolution of inflammation
  • • Immunometabolism
  • • Adaptive immunity
  • • Translational medicine
  • • Culture of neutrophil progenitors.

Published Papers (16 papers)

2022

17 pages, 2696 KiB  
Article
Human Neutrophils Generate Extracellular Vesicles That Modulate Their Functional Responses
by María José Hurtado Gutiérrez, Frédérick L. Allard, Hugo Tshivuadi Mosha, Claire M. Dubois and Patrick P. McDonald
Cells 2023, 12(1), 136; https://doi.org/10.3390/cells12010136 - 29 Dec 2022
Viewed by 2113
Abstract
Neutrophils influence innate and adaptive immunity by releasing various cytokines and chemokines, by generating neutrophil extracellular traps (NETs), and by modulating their own survival. Neutrophils also produce extracellular vesicles (EVs) termed ectosomes, which influence the function of other immune cells. Here, we studied [...] Read more.
Neutrophils influence innate and adaptive immunity by releasing various cytokines and chemokines, by generating neutrophil extracellular traps (NETs), and by modulating their own survival. Neutrophils also produce extracellular vesicles (EVs) termed ectosomes, which influence the function of other immune cells. Here, we studied neutrophil-derived ectosomes (NDEs) and whether they can modulate autologous neutrophil responses. We first characterized EV production by neutrophils, following MISEV 2018 guidelines to facilitate comparisons with other studies. We found that such EVs are principally NDEs, that they are rapidly released in response to several (but not all) physiological stimuli, and that a number of signaling pathways are involved in the induction of this response. When co-incubated with autologous neutrophils, NDE constituents were rapidly incorporated into recipient cells and this triggered and/or modulated neutrophil responses. The pro-survival effect of GM-CSF, G-CSF, IFNγ, and dexamethasone was reversed; CXCL8 and NET formation were induced in otherwise unstimulated neutrophils; the induction of inflammatory chemokines by TNFα was modulated depending on the activation state of the NDEs’ parent cells; and inducible NET generation was attenuated. Our data show that NDE generation modulates neutrophil responses in an autocrine and paracrine manner, and indicate that this probably represents an important aspect of how neutrophils shape their environment and cellular interactions. Full article
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26 pages, 3768 KiB  
Article
Functional Role of AGAP2/PIKE-A in Fcγ Receptor-Mediated Phagocytosis
by François C. Chouinard, Lynn Davis, Caroline Gilbert and Sylvain G. Bourgoin
Cells 2023, 12(1), 72; https://doi.org/10.3390/cells12010072 - 24 Dec 2022
Viewed by 1461
Abstract
In phagocytes, cytoskeletal and membrane remodeling is finely regulated at the phagocytic cup. Various smaFll G proteins, including those of the Arf family, control these dynamic processes. Human neutrophils express AGAP2, an Arf GTPase activating protein (ArfGAP) that regulates endosomal trafficking and focal [...] Read more.
In phagocytes, cytoskeletal and membrane remodeling is finely regulated at the phagocytic cup. Various smaFll G proteins, including those of the Arf family, control these dynamic processes. Human neutrophils express AGAP2, an Arf GTPase activating protein (ArfGAP) that regulates endosomal trafficking and focal adhesion remodeling. We first examined the impact of AGAP2 on phagocytosis in CHO cells stably expressing the FcγRIIA receptor (CHO-IIA). In unstimulated CHO-IIA cells, AGAP2 only partially co-localized with cytoskeletal elements and intracellular compartments. In CHO-IIA cells, AGAP2 transiently accumulated at actin-rich phagocytic cups and increased Fcγ receptor-mediated phagocytosis. Enhanced phagocytosis was not dependent on the N-terminal GTP-binding protein-like (GLD) domain of AGAP2. AGAP2 deleted of its GTPase-activating protein (GAP) domain was not recruited to phagocytic cups and did not enhance the engulfment of IgG-opsonized beads. However, the GAP-deficient [R618K]AGAP2 transiently localized at the phagocytic cups and enhanced phagocytosis. In PLB-985 cells differentiated towards a neutrophil-like phenotype, silencing of AGAP2 reduced phagocytosis of opsonized zymosan. In human neutrophils, opsonized zymosan or monosodium urate crystals induced AGAP2 phosphorylation. The data indicate that particulate agonists induce AGAP2 phosphorylation in neutrophils. This study highlights the role of AGAP2 and its GAP domain but not GAP activity in FcγR-dependent uptake of opsonized particles. Full article
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22 pages, 1714 KiB  
Article
The Association between Maternal Oral Inflammation and Neutrophil Phenotypes and Poly-Unsaturated Fatty Acids Composition in Human Milk: A Prospective Cohort Study
by Rana Badewy, Amir Azarpazhooh, Howard Tenenbaum, Kristin L. Connor, Jim Yuan Lai, Michael Sgro, Richard P. Bazinet, Noah Fine, Erin Watson, Chunxiang Sun, Sourav Saha and Michael Glogauer
Cells 2022, 11(24), 4110; https://doi.org/10.3390/cells11244110 - 17 Dec 2022
Cited by 1 | Viewed by 1907
Abstract
This prospective cohort study aimed to investigate the impact of maternal oral inflammation on human milk composition including neutrophil counts, activation state (based on cluster of differentiation (CD) markers expression), and fatty acid levels. Fifty mothers were recruited from St. Michael’s hospital, Toronto, [...] Read more.
This prospective cohort study aimed to investigate the impact of maternal oral inflammation on human milk composition including neutrophil counts, activation state (based on cluster of differentiation (CD) markers expression), and fatty acid levels. Fifty mothers were recruited from St. Michael’s hospital, Toronto, and followed up from 2–4 weeks until 4 months postpartum. Oral rinse and human milk samples were collected at both timepoints. Oral polymorphonuclear neutrophils (oPMNs) within the rinses were quantified using flow cytometry and the participants’ oral health state was categorized into three groups (i.e., healthy, moderate, and severe) based on the oPMNs counts. Fatty acids were identified and quantified using a gas chromatography-flame ionization detector (GC-FID). Compared to mothers with a healthy oral health state, mothers with moderate to severe oral inflammation had a statistically significant decrease in the expression of CD64 biomarker, an increase in the expression of CD14 biomarker on human milk neutrophils and a decrease in the levels of eicosapentaenoic acid (C20:5n-3) in their human milk at follow-up compared to baseline. This study demonstrates for the first time that maternal oral inflammation can affect human milk composition. The mechanism by which these alterations can affect infant health outcomes in the long term critically needs to be considered. Full article
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19 pages, 4268 KiB  
Article
SARS-CoV-2-Associated ssRNAs Activate Human Neutrophils in a TLR8-Dependent Fashion
by Elisa Gardiman, Francisco Bianchetto-Aguilera, Sara Gasperini, Laura Tiberio, Matteo Scandola, Virginia Lotti, Davide Gibellini, Valentina Salvi, Daniela Bosisio, Marco A. Cassatella and Nicola Tamassia
Cells 2022, 11(23), 3785; https://doi.org/10.3390/cells11233785 - 26 Nov 2022
Cited by 7 | Viewed by 1931
Abstract
COVID-19 disease is characterized by a dysregulation of the innate arm of the immune system. However, the mechanisms whereby innate immune cells, including neutrophils, become activated in patients are not completely understood. Recently, we showed that GU-rich RNA sequences from the SARS-CoV-2 genome [...] Read more.
COVID-19 disease is characterized by a dysregulation of the innate arm of the immune system. However, the mechanisms whereby innate immune cells, including neutrophils, become activated in patients are not completely understood. Recently, we showed that GU-rich RNA sequences from the SARS-CoV-2 genome (i.e., SCV2-RNA1 and SCV2-RNA2) activate dendritic cells. To clarify whether human neutrophils may also represent targets of SCV2-RNAs, neutrophils were treated with either SCV2-RNAs or, as a control, R848 (a TLR7/8 ligand), and were then analyzed for several functional assays and also subjected to RNA-seq experiments. Results highlight a remarkable response of neutrophils to SCV2-RNAs in terms of TNFα, IL-1ra, CXCL8 production, apoptosis delay, modulation of CD11b and CD62L expression, and release of neutrophil extracellular traps. By RNA-seq experiments, we observed that SCV2-RNA2 promotes a transcriptional reprogramming of neutrophils, characterized by the induction of thousands of proinflammatory genes, similar to that promoted by R848. Furthermore, by using CU-CPT9a, a TLR8-specific inhibitor, we found that SCV2-RNA2 stimulates neutrophils exclusively via TLR8-dependent pathways. In sum, our study proves that single-strand RNAs from the SARS-CoV-2 genome potently activate human neutrophils via TLR8, thus uncovering a potential mechanism whereby neutrophils may contribute to the pathogenesis of severe COVID-19 disease. Full article
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16 pages, 4416 KiB  
Article
Correlation between Neutrophil Extracellular Traps (NETs) Expression and Primary Graft Dysfunction Following Human Lung Transplantation
by Steven Bonneau, Caroline Landry, Stéphanie Bégin, Damien Adam, Louis Villeneuve, Marie-Élaine Clavet-Lanthier, Ariane Dasilva, Elcha Charles, Benjamin L. Dumont, Paul-Eduard Neagoe, Emmanuelle Brochiero, Ahmed Menaouar, Basil Nasir, Louis-Mathieu Stevens, Pasquale Ferraro, Nicolas Noiseux and Martin G. Sirois
Cells 2022, 11(21), 3420; https://doi.org/10.3390/cells11213420 - 29 Oct 2022
Cited by 7 | Viewed by 2152
Abstract
Primary graft dysfunction (PGD) is characterized by alveolar epithelial and vascular endothelial damage and inflammation, lung edema and hypoxemia. Up to one-third of recipients develop the most severe form of PGD (Grade 3; PGD3). Animal studies suggest that neutrophils contribute to the inflammatory [...] Read more.
Primary graft dysfunction (PGD) is characterized by alveolar epithelial and vascular endothelial damage and inflammation, lung edema and hypoxemia. Up to one-third of recipients develop the most severe form of PGD (Grade 3; PGD3). Animal studies suggest that neutrophils contribute to the inflammatory process through neutrophil extracellular traps (NETs) release (NETosis). NETs are composed of DNA filaments decorated with granular proteins contributing to vascular occlusion associated with PGD. The main objective was to correlate NETosis in PGD3 (n = 9) versus non-PGD3 (n = 27) recipients in an exploratory study. Clinical data and blood samples were collected from donors and recipients pre-, intra- and postoperatively (up to 72 h). Inflammatory inducers of NETs’ release (IL-8, IL-6 and C-reactive protein [CRP]) and components (myeloperoxidase [MPO], MPO-DNA complexes and cell-free DNA [cfDNA]) were quantified by ELISA. When available, histology, immunohistochemistry and immunofluorescence techniques were performed on lung biopsies from donor grafts collected during the surgery to evaluate the presence of activated neutrophils and NETs. Lung biopsies from donor grafts collected during transplantation presented various degrees of vascular occlusion including neutrophils undergoing NETosis. Additionally, in recipients intra- and postoperatively, circulating inflammatory (IL-6, IL-8) and NETosis biomarkers (MPO-DNA, MPO, cfDNA) were up to 4-fold higher in PGD3 recipients compared to non-PGD3 (p = 0.041 to 0.001). In summary, perioperative elevation of NETosis biomarkers is associated with PGD3 following human lung transplantation and these biomarkers might serve to identify recipients at risk of PGD3 and initiate preventive therapies. Full article
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12 pages, 1987 KiB  
Article
Effective, Long-Term, Neutrophil Depletion Using a Murinized Anti-Ly-6G 1A8 Antibody
by Patricia A. Olofsen, Marjolein C. Stip, J. H. Marco Jansen, Chilam Chan, Maaike Nederend, Ralph G. Tieland, Maria Tsioumpekou and Jeanette H. W. Leusen
Cells 2022, 11(21), 3406; https://doi.org/10.3390/cells11213406 - 27 Oct 2022
Cited by 1 | Viewed by 4530
Abstract
Neutrophils are crucial innate immune cells but also play key roles in various diseases, such as cancer, where they can perform both pro- and anti-tumorigenic functions. To study the function of neutrophils in vivo, these cells are often depleted using Ly-6G or Gr-1 [...] Read more.
Neutrophils are crucial innate immune cells but also play key roles in various diseases, such as cancer, where they can perform both pro- and anti-tumorigenic functions. To study the function of neutrophils in vivo, these cells are often depleted using Ly-6G or Gr-1 depleting antibodies or genetic “knockout” models. However, these methods have several limitations, being only partially effective, effective for a short term, and lacking specificity or the ability to conditionally deplete neutrophils. Here, we describe the use of a novel murinized Ly-6G (1A8) antibody. The murinized Ly-6G antibody is of the mouse IgG2a isotype, which is the only isotype that can bind all murine Fcγ receptors and C1q and is, therefore, able to activate antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC) pathways. We show that this mouse-Ly-6G antibody shows efficient, long-term, and near-complete (>90%) neutrophil depletion in the peripheral blood of C57Bl6/J, Balb/c, NXG and SCID mice for up to at least four weeks, using a standardized neutrophil depletion strategy. In addition, we show that neutrophils are efficiently depleted in the blood and tumor tissue of IMR32 tumor-bearing SCID mice, analyzed six weeks after the start of the treatment. Full article
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17 pages, 3248 KiB  
Article
Neutrophil Extracellular Vesicles and Airway Smooth Muscle Proliferation in the Natural Model of Severe Asthma in Horses
by Sophie Mainguy-Seers, Francis Beaudry, Christopher Fernandez-Prada, James G. Martin and Jean-Pierre Lavoie
Cells 2022, 11(21), 3347; https://doi.org/10.3390/cells11213347 - 24 Oct 2022
Cited by 3 | Viewed by 2088
Abstract
Extracellular vesicles (EVs) contribute to intercellular communication through the transfer of their rich cargo to recipient cells. The EVs produced by LPS-stimulated neutrophils from healthy humans and horses increase airway smooth muscle (ASM) proliferation, but the roles of neutrophil EVs in asthma are [...] Read more.
Extracellular vesicles (EVs) contribute to intercellular communication through the transfer of their rich cargo to recipient cells. The EVs produced by LPS-stimulated neutrophils from healthy humans and horses increase airway smooth muscle (ASM) proliferation, but the roles of neutrophil EVs in asthma are largely unexplored. The aim of this study was to determine whether neutrophil-derived EVs isolated during the remission or exacerbation of asthma influence ASM proliferation differentially. Peripheral blood neutrophils were collected during remission and exacerbation in eight horses affected by severe asthma. The cells were cultured (±LPS), and their EVs were isolated by ultracentrifugation and characterized by laser scattering microscopy and proteomic analysis. The proliferation of ASM co-incubated with EVs was monitored in real time by electrical impedance. Two proteins were significantly upregulated during disease exacerbation in neutrophil EVs (MAST4 and Lrch4), while LPS stimulation greatly altered the proteomic profile. Those changes involved the upregulation of neutrophil degranulation products, including proteases known to induce myocyte proliferation. In agreement with the proteomic results, EVs from LPS-stimulated neutrophils increased ASM proliferation, without an effect of the disease status. The inhalation of environmental LPS could contribute to asthma pathogenesis by activating neutrophils and leading to ASM hyperplasia. Full article
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19 pages, 1671 KiB  
Review
Neutrophil Extracellular Vesicles: A Delicate Balance between Pro-Inflammatory Responses and Anti-Inflammatory Therapies
by Yang Zhou and Sabrina Bréchard
Cells 2022, 11(20), 3318; https://doi.org/10.3390/cells11203318 - 21 Oct 2022
Cited by 8 | Viewed by 3326
Abstract
Extracellular vesicles (EVs) are released in the extracellular environment during cell activation or apoptosis. Working as signal transducers, EVs are important mediators of intercellular communication through the convoying of proteins, nucleic acids, lipids, and metabolites. Neutrophil extracellular vesicles (nEVs) contain molecules acting as [...] Read more.
Extracellular vesicles (EVs) are released in the extracellular environment during cell activation or apoptosis. Working as signal transducers, EVs are important mediators of intercellular communication through the convoying of proteins, nucleic acids, lipids, and metabolites. Neutrophil extracellular vesicles (nEVs) contain molecules acting as key modulators of inflammation and immune responses. Due to their potential as therapeutic tools, studies about nEVs have been increasing in recent years. However, our knowledge about nEVs is still in its infancy. In this review, we summarize the current understanding of the role of nEVs in the framework of neutrophil inflammation functions and disease development. The therapeutic potential of nEVs as clinical treatment strategies is deeply discussed. Moreover, the promising research landscape of nEVs in the near future is also examined. Full article
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11 pages, 625 KiB  
Review
Morbidity and Mortality of Neutropenic Patients in Visceral Surgery: A Narrative Review
by Ann-Kathrin Lederer, Fabian Bartsch, Markus Moehler, Peter Gaßmann and Hauke Lang
Cells 2022, 11(20), 3314; https://doi.org/10.3390/cells11203314 - 21 Oct 2022
Cited by 2 | Viewed by 2119
Abstract
Leukocytes are essential for the function of the immune system and cell–cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are [...] Read more.
Leukocytes are essential for the function of the immune system and cell–cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are neutrophilic granulocytes, and leukopenia is, therefore, mostly characterized by a decrease in neutrophilic granulocytes. The consequence of neutropenia is increased susceptibility to infection, but also healing disorders are suggestable due to the disturbed cell–cell interaction. While there is no surgical treatment for leucocyte disorders, patients suffering from neutropenia are sometimes in need of surgery for other reasons. Less is known about the morbidity and mortality of this patients, which is why this narrative review critically summarizes the results of recent research in this particular field. The results of this review suggest that neutropenic patients in need of emergency surgery have a higher mortality risk compared to non-neutropenic patients. In contrast, in elective surgery, there was not a clear tendency for a higher mortality risk of neutropenic patients. The role of neutrophilic granulocytes in inflammation and immunity in surgical patients is emphasized by the results, but most of the evaluated studies showed methodological flaws due to small sample sizes or risk of bias. Further research has to evaluate the risk for postoperative complications, particularly of infectious complications such as surgical site infections, in neutropenic patients undergoing elective surgery, and should address the role of neutrophilic function in postoperative morbidity and mortality. Full article
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19 pages, 1041 KiB  
Review
Neutrophil Activated by the Famous and Potent PMA (Phorbol Myristate Acetate)
by Hylane Luiz Damascena, Wendy Ann Assis Silveira, Mariana S. Castro and Wagner Fontes
Cells 2022, 11(18), 2889; https://doi.org/10.3390/cells11182889 - 16 Sep 2022
Cited by 24 | Viewed by 4188
Abstract
This review will briefly outline the major signaling pathways in PMA-activated neutrophils. PMA is widely used to understand neutrophil pathways and formation of NETs. PMA activates PKC; however, we highlight some isoforms that contribute to specific functions. PKC α, β and δ contribute [...] Read more.
This review will briefly outline the major signaling pathways in PMA-activated neutrophils. PMA is widely used to understand neutrophil pathways and formation of NETs. PMA activates PKC; however, we highlight some isoforms that contribute to specific functions. PKC α, β and δ contribute to ROS production while PKC βII and PKC ζ are involved in cytoskeleton remodeling. Actin polymerization is important for the chemotaxis of neutrophils and its remodeling is connected to ROS balance. We suggest that, although ROS and production of NETs are usually observed together in PMA-activated neutrophils, there might be a regulatory mechanism balancing both. Interestingly, we suggest that serine proteases might determine the PAD4 action. PAD4 could be responsible for the activation of the NF-κB pathway that leads to IL-1β release, triggering the cleavage of gasdermin D by serine proteases such as elastase, leading to pore formation contributing to release of NETs. On the other hand, when serine proteases are inhibited, NETs are formed by citrullination through the PAD4 pathway. This review puts together results from the last 31 years of research on the effects of PMA on the neutrophil and proposes new insights on their interpretation. Full article
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16 pages, 1228 KiB  
Article
hMRP8-ATTAC Mice: A New Model for Conditional and Reversible Neutrophil Ablation
by Danique E. M. Duits, Camilla Salvagno, Elisabeth A. M. Raeven, Kim Vrijland, Marjolein C. Stip, Cheei-Sing Hau, Daphne Kaldenbach and Karin E. de Visser
Cells 2022, 11(15), 2346; https://doi.org/10.3390/cells11152346 - 30 Jul 2022
Viewed by 1897
Abstract
Neutrophils are not only crucial immune cells for the neutralization of pathogens during infections, but they are also key players in tissue repair and cancer. Several methods are available to investigate the in vivo role of neutrophils in these conditions, including the depletion [...] Read more.
Neutrophils are not only crucial immune cells for the neutralization of pathogens during infections, but they are also key players in tissue repair and cancer. Several methods are available to investigate the in vivo role of neutrophils in these conditions, including the depletion of neutrophils with neutralizing antibodies against Ly6G, or the blockade of neutrophil recruitment with CXCR2 inhibitors. A limited number of transgenic mouse models were generated that rely on the disruption of genes important for neutrophil development or on the injection of diphtheria toxin to induce neutrophil ablation. However, these methods have various limitations, including a lack of neutrophil specificity, a lack of long-term efficacy, or a lack of the ability to conditionally deplete neutrophils. Therefore, we generated a transgenic mouse model for the inducible and reversible ablation of neutrophils using the ATTAC (Apoptosis Through Targeted Activation of Caspase 8) approach. With the ATTAC strategy, which relies on the expression of the caspase 8-FKBP fusion protein, apoptosis is induced upon administration of a chemical dimerizer (FK506 analogue) that facilitates the dimerization and activation of caspase 8. In order to achieve specific neutrophil depletion, we cloned the ATTAC construct under the human migration inhibitory factor-related protein 8 (hMRP8) promotor. The newly generated hMRP8-ATTAC mice expressed high levels of the transgene in neutrophils, and, as a consequence, dimerizer injection induced an efficient reduction of neutrophil levels in all the organs analyzed under homeostatic conditions. In situations with extensive pressure on the bone marrow to mobilize neutrophils, for instance in the context of cancer, effective neutrophil depletion in this model requires further optimization. In conclusion, we here describe the generation and characterization of a new transgenic model for conditional neutrophil ablation and highlight the need to improve the ATTAC strategy for the depletion of large numbers of rapidly generated short-lived cells, such as neutrophils. Full article
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11 pages, 1254 KiB  
Article
Neutrophils Promote Glioblastoma Tumor Cell Migration after Biopsy
by Na Chen, Maria Alieva, Tom van der Most, Joelle A. Z. Klazen, Arabel Vollmann-Zwerenz, Peter Hau and Nienke Vrisekoop
Cells 2022, 11(14), 2196; https://doi.org/10.3390/cells11142196 - 14 Jul 2022
Cited by 6 | Viewed by 2039
Abstract
Glioblastoma is diagnosed by biopsy or, if clinically feasible, tumor resection. However, emerging evidence suggests that this surgical intervention may increase the risk of tumor cell spread. It has been hypothesized that the damage to the tumor leads to infiltration of immune cells [...] Read more.
Glioblastoma is diagnosed by biopsy or, if clinically feasible, tumor resection. However, emerging evidence suggests that this surgical intervention may increase the risk of tumor cell spread. It has been hypothesized that the damage to the tumor leads to infiltration of immune cells that consequently form an environment that favors tumor cell motility. In mouse glioma models, it was previously found that biopsy induced migration of tumor cells in vivo and that recruitment of monocytes from the blood was involved in this effect. However, the role of neutrophils in this process is still unclear. Here, we study the contribution of neutrophils on the pro-migratory effect of surgical interventions in glioma. Using repetitive intravital microscopy, in vivo migration of glioma tumor cells before and after biopsy was compared in mice systemically depleted of neutrophils. Interestingly, macrophages/microglia were almost completely absent from neutrophil-depleted tumors, indicating that neutrophils may be indirectly involved in biopsy-induced migration of glioma tumor cells through the recruitment of macrophages to the tumor. To further investigate whether neutrophils have the potential to also directly promote glioblastoma tumor cell migration, we performed in vitro migration assays using human neutrophils. Indeed, wound-healing of human primary glioblastoma tumor cell lines was promoted by human neutrophils. The pro-migratory effects of human neutrophils on glioblastoma tumor cells could also be recapitulated in transwell migration assays, indicating that soluble factor(s) are involved. We therefore provide evidence for both an indirect and direct involvement of neutrophils in tumor spread following biopsy of glioblastoma tumors. Full article
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27 pages, 2944 KiB  
Review
Neutrophils Actively Contribute to Obesity-Associated Inflammation and Pathological Complications
by Eileen Uribe-Querol and Carlos Rosales
Cells 2022, 11(12), 1883; https://doi.org/10.3390/cells11121883 - 10 Jun 2022
Cited by 31 | Viewed by 4651
Abstract
Obesity is characterized by an increase in body weight associated with an exaggerated enlargement of the adipose tissue. Obesity has serious negative effects because it is associated with multiple pathological complications such as type 2 diabetes mellitus, cardiovascular diseases, cancer, and COVID-19. Nowadays, [...] Read more.
Obesity is characterized by an increase in body weight associated with an exaggerated enlargement of the adipose tissue. Obesity has serious negative effects because it is associated with multiple pathological complications such as type 2 diabetes mellitus, cardiovascular diseases, cancer, and COVID-19. Nowadays, 39% of the world population is obese or overweight, making obesity the 21st century epidemic. Obesity is also characterized by a mild, chronic, systemic inflammation. Accumulation of fat in adipose tissue causes stress and malfunction of adipocytes, which then initiate inflammation. Next, adipose tissue is infiltrated by cells of the innate immune system. Recently, it has become evident that neutrophils, the most abundant leukocytes in blood, are the first immune cells infiltrating the adipose tissue. Neutrophils then get activated and release inflammatory factors that recruit macrophages and other immune cells. These immune cells, in turn, perpetuate the inflammation state by producing cytokines and chemokines that can reach other parts of the body, creating a systemic inflammatory condition. In this review, we described the recent findings on the role of neutrophils during obesity and the initiation of inflammation. In addition, we discuss the involvement of neutrophils in the generation of obesity-related complications using diabetes as a prime example. Full article
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21 pages, 6743 KiB  
Article
Plasma Proteomic Analysis Identified Proteins Associated with Faulty Neutrophils Functionality in Decompensated Cirrhosis Patients with Sepsis
by Rashi Sehgal, Navkiran Kaur, Rakhi Maiwall, Gayatri Ramakrishna, Jaswinder Singh Maras and Nirupma Trehanpati
Cells 2022, 11(11), 1745; https://doi.org/10.3390/cells11111745 - 25 May 2022
Cited by 10 | Viewed by 2999
Abstract
Decompensated cirrhosis (DC) is susceptible to infections and sepsis. Neutrophils and monocytes provide the first line of defense to encounter infection. We aimed to evaluate proteins related to neutrophils functionality in sepsis. 70 (DC), 40 with sepsis, 30 without (w/o [...] Read more.
Decompensated cirrhosis (DC) is susceptible to infections and sepsis. Neutrophils and monocytes provide the first line of defense to encounter infection. We aimed to evaluate proteins related to neutrophils functionality in sepsis. 70 (DC), 40 with sepsis, 30 without (w/o) sepsis and 15 healthy controls (HC) plasma was analyzed for proteomic analysis, cytokine bead array, endotoxin, cell free DNA and whole blood cells were analyzed for nCD64-mHLADR index, neutrophils-monocytes, functionality and QRT-PCR. nCD64-mHLADR index was significantly increased (p < 0.0001) with decreased HLA-DR expression on total monocytes in sepsis (p = 0.045). Phagocytic activity of both neutrophils and monocytes were significantly decreased in sepsis (p = 0.002 and p = 0.0003). Sepsis plasma stimulated healthy neutrophils, showed significant increase in NETs (neutrophil extracellular traps) and cell free DNA (p = 0.049 and p = 0.04) compared to w/o sepsis and HC. Proteomic analysis revealed upregulated- DNAJC13, TMSB4X, GPI, GSTP1, PNP, ANPEP, COTL1, GCA, APOA1 and PGAM1 while downregulated- AHSG, DEFA1,SERPINA3, MPO, MMRN1and PROS1 proteins (FC > 1.5; p < 0.05) associated to neutrophil activation and autophagy in sepsis. Proteins such as DNAJC13, GPI, GSTP1, PNP, ANPEP, COTL1, PGAM1, PROS1, MPO, SERPINA3 and MMRN1 showed positive correlation with neutrophils activity and number, oxidative burst activity and clinical parameters such as MELD, MELD Na and Bilirubin. Proteomic analysis revealed that faulty functionality of neutrophils may be due to the autophagy proteins i.e., DNAJC13, AHSG, TMSB4X, PROS1 and SERPINA3, which can be used as therapeutic targets in decompensated cirrhosis patients with sepsis. Full article
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12 pages, 19692 KiB  
Article
TGF-β1 Reduces Neutrophil Adhesion and Prevents Acute Vaso-Occlusive Processes in Sickle Cell Disease Mice
by Lidiane S. Torres, Hanan Chweih, Fernanda C. Z. Fabris, Erica M. F. Gotardo, Flávia C. Leonardo, Sara T. Olalla Saad, Fernando F. Costa and Nicola Conran
Cells 2022, 11(7), 1200; https://doi.org/10.3390/cells11071200 - 2 Apr 2022
Cited by 5 | Viewed by 2810
Abstract
Sickle cell disease (SCD) patients experience chronic inflammation and recurrent vaso-occlusive episodes during their entire lifetime. Inflammation in SCD occurs with the overexpression of several inflammatory mediators, including transforming growth factor beta-1 (TGF-β1), a major immune regulator. In this study, we aimed to [...] Read more.
Sickle cell disease (SCD) patients experience chronic inflammation and recurrent vaso-occlusive episodes during their entire lifetime. Inflammation in SCD occurs with the overexpression of several inflammatory mediators, including transforming growth factor beta-1 (TGF-β1), a major immune regulator. In this study, we aimed to investigate the role played by TGF-β1 in vascular inflammation and vaso-occlusion in an animal model of SCD. Using intravital microscopy, we found that a daily dose of recombinant TGF-β1 administration for three consecutive days significantly reduced TNFα-induced leukocyte rolling, adhesion, and extravasation in the microcirculation of SCD mice. In contrast, immunological neutralization of TGF-β, in the absence of inflammatory stimulus, considerably increased these parameters. Our results indicate, for the first time, that TGF-β1 may play a significant ameliorative role in vascular SCD pathophysiology, modulating inflammation and vaso-occlusion. The mechanisms by which TGF-β1 exerts its anti-inflammatory effects in SCD, however, remains unclear. Our in vitro adhesion assays with TNFα-stimulated human neutrophils suggest that TGF-β1 can reduce the adhesive properties of these cells; however, direct effects of TGF-β1 on the endothelium cannot be ruled out. Further investigation of the wide range of the complex biology of this cytokine in SCD pathophysiology and its potential therapeutical use is needed. Full article
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26 pages, 4395 KiB  
Article
Sevoflurane Dampens Acute Pulmonary Inflammation via the Adenosine Receptor A2B and Heme Oxygenase-1
by Kristian-Christos Ngamsri, Anika Fuhr, Katharina Schindler, Mariana Simelitidis, Michelle Hagen, Yi Zhang, Jutta Gamper-Tsigaras and Franziska M. Konrad
Cells 2022, 11(7), 1094; https://doi.org/10.3390/cells11071094 - 24 Mar 2022
Cited by 4 | Viewed by 2073
Abstract
Acute respiratory distress syndrome is a life-threatening disease associated with high mortality. The adenosine receptor A2B (Adora2b) provides anti-inflammatory effects, which are also associated with the intracellular enzyme heme oxygenase-1 (HO-1). Our study determined the mechanism of sevoflurane’s protective properties and investigated the [...] Read more.
Acute respiratory distress syndrome is a life-threatening disease associated with high mortality. The adenosine receptor A2B (Adora2b) provides anti-inflammatory effects, which are also associated with the intracellular enzyme heme oxygenase-1 (HO-1). Our study determined the mechanism of sevoflurane’s protective properties and investigated the link between sevoflurane and the impact of a functional Adora2b via HO-1 modulation during lipopolysaccharide (LPS)-induced lung injury. We examined the LPS-induced infiltration of polymorphonuclear neutrophils (PMNs) into the lung tissue and protein extravasation in wild-type and Adora2b−/− animals. We generated chimeric animals, to identify the impact of sevoflurane on Adora2b of hematopoietic and non-hematopoietic cells. Sevoflurane decreased the LPS-induced PMN-infiltration and diminished the edema formation in wild-type mice. Reduced PMN counts after sevoflurane treatment were detected only in chimeric mice, which expressed Adora2b exclusively on leukocytes. The Adora2b on hematopoietic and non-hematopoietic cells was required to improve the permeability after sevoflurane inhalation. Further, sevoflurane increased the protective effects of HO-1 modulation on PMN migration and microvascular permeability. These protective effects were abrogated by specific HO-1 inhibition. In conclusion, our data revealed new insights into the protective mechanisms of sevoflurane application during acute pulmonary inflammation and the link between sevoflurane and Adora2b, and HO-1 signaling, respectively. Full article
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