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New Insights into Neutrophil Biology
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New Insights into Neutrophil Biology

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (20 November 2022) | Viewed by 17527

Special Issue Editors

Dr. Lynne Prince

E-Mail Website
Guest Editor
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
Interests: neutrophil cell death; inflammation; infection
Prof. Dr. Adriano Rossi

E-Mail Website
Guest Editor
MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
Interests: neutrophil apoptosis and clearance
Dr. Jon Hazeldine

E-Mail Website
Guest Editor
NIHR Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital Birmingham, Birmingham, UK
Interests: innate immunity; immunosuppression; immunosenescence

Special Issue Information

Dear Colleagues,

Our understanding of the roles played by neutrophils in health and disease continues to grow as we discover more about the functionality of these critical innate immune cells. Neutrophils are rapidly recruited to sites of infection, inflammation and injury and subsequently carry out an array of effector functions to counteract the initial insult. These cellular actions primarily serve to limit bacterial invasion, but can also promote healing in sterile tissues. However, dysregulated neutrophil responses can lead to significant tissue damage and non-resolving inflammation as observed in chronic diseases of the airway, vasculature, gut and other systems. Targeting neutrophils as a potential therapeutic strategy continues to be an area of intense research. This is not without its challenges, but the contribution of neutrophils across multiple pathologies means that a breakthrough in this area could have significant clinical benefit on a global scale.

The aim of this Special Issue is to present the latest insights on neutrophil biology in health and disease, covering areas including migration, immunity, pathogen interactions, cell death programmes, plasticity, cancer, inflammation (and inflammation resolution) and wound healing.

Dr. Lynne Prince
Prof. Dr. Adriano Rossi
Dr. Jon Hazeldine
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • apoptosis
  • NETosis
  • infection
  • inflammation
  • disease
  • proteomics
  • transcriptomics
  • migration
  • neutrophil heterogeneity
  • epigenetics
  • metabolism
  • wound healing

Published Papers (5 papers)

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Research

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22 pages, 4508 KiB  
Article
NET Proteome in Established Type 1 Diabetes Is Enriched in Metabolic Proteins
by Samal Bissenova, Darcy Ellis, Aïsha Callebaut, Guy Eelen, Rita Derua, Mijke Buitinga, Chantal Mathieu, Conny Gysemans and Lut Overbergh
Cells 2023, 12(9), 1319; https://doi.org/10.3390/cells12091319 - 05 May 2023
Cited by 2 | Viewed by 1890
Abstract
Background and aims: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by a T-cell-mediated destruction of the pancreatic insulin-producing beta cells. A growing body of evidence suggests that abnormalities in neutrophils and neutrophil extracellular trap (NET) formation (NETosis) are associated with [...] Read more.
Background and aims: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by a T-cell-mediated destruction of the pancreatic insulin-producing beta cells. A growing body of evidence suggests that abnormalities in neutrophils and neutrophil extracellular trap (NET) formation (NETosis) are associated with T1D pathophysiology. However, little information is available on whether these changes are primary neutrophil defects or related to the environmental signals encountered during active disease. Methods: In the present work, the NET proteome (NETome) of phorbol 12-myristate 13-acetate (PMA)- and ionomycin-stimulated neutrophils from people with established T1D compared to healthy controls (HC) was studied by proteomic analysis. Results: Levels of NETosis, in addition to plasma levels of pro-inflammatory cytokines and NET markers, were comparable between T1D and HC subjects. However, the T1D NETome was distinct from that of HC in response to both stimuli. Quantitative analysis revealed that the T1D NETome was enriched in proteins belonging to metabolic pathways (i.e., phosphoglycerate kinase, glyceraldehyde-3-phosphate dehydrogenase, and UTP-glucose-1-phosphate uridylyltransferase). Complementary metabolic profiling revealed that the rate of extracellular acidification, an approximate measure for glycolysis, and mitochondrial respiration were similar between T1D and HC neutrophils in response to both stimuli. Conclusion: The NETome of people with established T1D was enriched in metabolic proteins without an apparent alteration in the bio-energetic profile or dysregulated NETosis. This may reflect an adaptation mechanism employed by activated T1D neutrophils to avoid impaired glycolysis and consequently excessive or suboptimal NETosis, pivotal in innate immune defence and the resolution of inflammation. Full article
(This article belongs to the Special Issue New Insights into Neutrophil Biology)
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17 pages, 4679 KiB  
Article
Multiparametric Profiling of Neutrophil Function via a High-Throughput Flow Cytometry-Based Assay
by Kyle D. Timmer, Daniel J. Floyd, Allison K. Scherer, Arianne J. Crossen, Johnny Atallah, Adam L. Viens, David B. Sykes and Michael K. Mansour
Cells 2023, 12(5), 743; https://doi.org/10.3390/cells12050743 - 25 Feb 2023
Cited by 2 | Viewed by 5066
Abstract
Neutrophils are a vital component of the innate immune system and play an essential function in the recognition and clearance of bacterial and fungal pathogens. There is great interest in understanding mechanisms of neutrophil dysfunction in the setting of disease and deciphering potential [...] Read more.
Neutrophils are a vital component of the innate immune system and play an essential function in the recognition and clearance of bacterial and fungal pathogens. There is great interest in understanding mechanisms of neutrophil dysfunction in the setting of disease and deciphering potential side effects of immunomodulatory drugs on neutrophil function. We developed a high throughput flow cytometry-based assay for detecting changes to four canonical neutrophil functions following biological or chemical triggers. Our assay detects neutrophil phagocytosis, reactive oxygen species (ROS) generation, ectodomain shedding, and secondary granule release in a single reaction mixture. By selecting fluorescent markers with minimal spectral overlap, we merge four detection assays into one microtiter plate-based assay. We demonstrate the response to the fungal pathogen, Candida albicans and validate the assay’s dynamic range using the inflammatory cytokines G-CSF, GM-CSF, TNFα, and IFNγ. All four cytokines increased ectodomain shedding and phagocytosis to a similar degree while GM-CSF and TNFα were more active in degranulation when compared to IFNγ and G-CSF. We further demonstrated the impact of small molecule inhibitors such as kinase inhibition downstream of Dectin-1, a critical lectin receptor responsible for fungal cell wall recognition. Bruton’s tyrosine kinase (Btk), Spleen tyrosine kinase (Syk), and Src kinase inhibition suppressed all four measured neutrophil functions but all functions were restored with lipopolysaccharide co-stimulation. This new assay allows for multiple comparisons of effector functions and permits identification of distinct subpopulations of neutrophils with a spectrum of activity. Our assay also offers the potential for studying the intended and off-target effects of immunomodulatory drugs on neutrophil responses. Full article
(This article belongs to the Special Issue New Insights into Neutrophil Biology)
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20 pages, 2579 KiB  
Article
Dysregulated Neutrophil Phenotype and Function in Hospitalised Non-ICU COVID-19 Pneumonia
by Kylie B. R. Belchamber, Onn S. Thein, Jon Hazeldine, Frances S. Grudzinska, Aduragbemi A. Faniyi, Michael J. Hughes, Alice E. Jasper, Kay Por Yip, Louise E. Crowley, Sebastian T. Lugg, Elizabeth Sapey, Dhruv Parekh, David R. Thickett and Aaron Scott
Cells 2022, 11(18), 2901; https://doi.org/10.3390/cells11182901 - 16 Sep 2022
Cited by 8 | Viewed by 3203
Abstract
Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may [...] Read more.
Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP). Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients. Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p < 0.0001). The percentage of CD54+ neutrophils (p < 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p < 0.0001). The ex vivo inhibition of PI3K γ and δ reduced NET release by COVID-19 neutrophils (p = 0.0129). Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity. Full article
(This article belongs to the Special Issue New Insights into Neutrophil Biology)
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12 pages, 1697 KiB  
Article
Human Amniotic Membrane Mesenchymal Stem Cell-Synthesized PGE2 Exerts an Immunomodulatory Effect on Neutrophil Extracellular Trap in a PAD-4-Dependent Pathway through EP2 and EP4
by Gibrán Alejandro Estúa-Acosta, Beatriz Buentello-Volante, Fátima Sofía Magaña-Guerrero, José Eduardo-Aguayo Flores, Oscar Vivanco-Rojas, Ilse Castro-Salas, Karla Zarco-Ávila, Mariana A. García-Mejía and Yonathan Garfias
Cells 2022, 11(18), 2831; https://doi.org/10.3390/cells11182831 - 10 Sep 2022
Cited by 6 | Viewed by 1657
Abstract
Human amniotic membrane mesenchymal stem cells (hAM-MSC) secrete a myriad of components with immunosuppressive activities. In the present research, we aimed to describe the effect of prostaglandin E2 (PGE2) secreted by hAM-MSCs on neutrophil extracellular trap (NET) release and to [...] Read more.
Human amniotic membrane mesenchymal stem cells (hAM-MSC) secrete a myriad of components with immunosuppressive activities. In the present research, we aimed to describe the effect of prostaglandin E2 (PGE2) secreted by hAM-MSCs on neutrophil extracellular trap (NET) release and to characterize the role of its receptors (EP2/EP4) in PAD-4 and NFκB activity in neutrophils. Human peripheral blood neutrophils were ionomycin-stimulated in the presence of hAM-MSC conditioned medium (CM) treated or not with the selective PGE2 inhibitor MF-63, PGE2, EP2/EP4 agonists, and the selective PAD-4 inhibitor GSK-484. NET release, PAD-4, and NFκB activation were analyzed. Ionomycin induced NET release, which was inhibited in the presence of hAM-MSC-CM, while CM from hAM-MSCs treated with MF-63 prevented NET release inhibition. PGE2 and EP2/EP4 agonists, and GSK-484 inhibited NET release. EP2/EP4 agonists and GSK-484 inhibited H3-citrullination but did not affect PAD-4 protein expression. Finally, PGE2 and EP2/EP4 agonists and GSK-484 increased NFκB phosphorylation. Taken together, these results suggest that hAM-MSC exert their immunomodulatory activities through PGE2, inhibiting NET release in a PAD-4-dependent pathway. This research proposes a new mechanism by which hAM-MSC exert their activities when modulating the innate immune response and inhibiting NET release. Full article
(This article belongs to the Special Issue New Insights into Neutrophil Biology)
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Review

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15 pages, 985 KiB  
Review
Anti-Inflammatory Neutrophil Functions in the Resolution of Inflammation and Tissue Repair
by Waywen Loh and Sonja Vermeren
Cells 2022, 11(24), 4076; https://doi.org/10.3390/cells11244076 - 16 Dec 2022
Cited by 11 | Viewed by 5017
Abstract
Neutrophils are highly abundant circulating leukocytes that are amongst the first cells to be recruited to sites of infection or sterile injury. Their ability to generate and release powerful cytotoxic products ties with their role in host defence from bacterial and fungal infections. [...] Read more.
Neutrophils are highly abundant circulating leukocytes that are amongst the first cells to be recruited to sites of infection or sterile injury. Their ability to generate and release powerful cytotoxic products ties with their role in host defence from bacterial and fungal infections. Neutrophilic inflammation is tightly regulated to limit the amount of ‘bystander injury’ caused. Neutrophils were in the past regarded as short-lived, indiscriminate killers of invading microorganisms. However, this view has changed quite dramatically in recent years. Amongst other insights, neutrophils are now recognised to also have important anti-inflammatory functions that are critical for the resolution of inflammation and return to homeostasis. This minireview focusses on anti-inflammatory neutrophil functions, placing a particular focus on recent findings linked to neutrophil cell death, several types of which may be anti-inflammatory (apoptosis, secondary necrosis, and neutrophil extracellular traps). These are discussed together with features that may further promote the clearance of dead cells by efferocytosis and reprogramming of macrophages to promote resolution and repair. Full article
(This article belongs to the Special Issue New Insights into Neutrophil Biology)
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