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The Impact of Hypoxia on Neutrophil Signaling and Function

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 October 2020) | Viewed by 27328

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Special Issue Editors

Prof. Dr. Alison Condliffe

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Guest Editor

Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UK
Interests: neutrophil biology; hypoxia; respiratory (oxidative) burst; degranulation; priming; bactieral killing; PI3 kinase signaling; respiratory infection; immune deficiency; inflammatory lung disease

Dr. Philip Elks

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Guest Editor

Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UK
Interests: hypoxia, HIF signaling, tuberculosis, neutrophil biology, inflammation, cytokine signaling, nitric oxide, zebrafish

Dr. Roger Thompson

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Guest Editor

Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UK
Interests: hypoxia, neutrophil biology, host-pathogen interactions, inflammation, damage signaling, pulmonary vascular remodeling

Dr. Pranvera Sadiku

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Guest Editor

Queen's Medical Research Institute, The University of Edinburgh, Scotland, UK
Interests: Inflammation and Immunometabolism

Special Issue Information

Dear Colleagues,

Molecular oxygen is essential for the development and growth of multicellular organisms. Tissue oxygen tensions reflect a balance between oxygen delivery mechanisms and oxygen consumption, with each tissue compartment having a set-point which may be perturbed by a range of pathological processes (e.g., interruption of blood supply, infection, inflammation, malignancy).

Neutrophils are highly mobile and accumulate rapidly in response to such pathological insults, hence they must operate within a wide and rapidly changing range of oxygen tensions. They are therefore highly adapted to function in the setting of limited oxygen availability, swiftly modifying their cellular signaling pathways and functional properties. Such adaptations may profoundly affect the interaction of these professional phagocytes with their environment, altering outcomes in a range of inflammatory scenarios. Hypoxia inducible factors (HIFs) are transcription factors which function as key molecular regulators of hypoxic responses, but it is increasingly recognized that HIF regulation of neutrophil function integrates other micro-environmental cues alongside hypoxia and that HIF-independent pathways may also influence the neutrophil’s response to hypoxia.

This Special Issue focuses on the recent advances in our understanding of the biology of hypoxia signaling and its impact on neutrophil function and interactions with the inflammatory microenvironment, in particular in the setting of infection and malignancy.

Prof. Dr. Alison Condliffe
Dr. Philip Elks
Dr. Roger Thompson
Dr. Pranvera Sadiku
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Hypoxia
Neutrophil
Oxygen sensing
Hypoxia inducible factor (HIF)
Microenvironment
Host-pathogen interaction

Published Papers (5 papers)

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Research

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29 pages, 2019 KiB

Open AccessArticle

Phosphoproteomic Analysis of Rat Neutrophils Shows the Effect of Intestinal Ischemia/Reperfusion and Preconditioning on Kinases and Phosphatases

by Muhammad Tahir, Samina Arshid, Belchor Fontes, Mariana S. Castro, Simone Sidoli, Veit Schwämmle, Isabelle S. Luz, Peter Roepstorff and Wagner Fontes

Int. J. Mol. Sci. 2020, 21(16), 5799; https://doi.org/10.3390/ijms21165799 - 13 Aug 2020

Cited by 6 | Viewed by 3226

Abstract

Intestinal ischemia reperfusion injury (iIRI) is a severe clinical condition presenting high morbidity and mortality worldwide. Some of the systemic consequences of IRI can be prevented by applying ischemic preconditioning (IPC), a series of short ischemia/reperfusion events preceding the major ischemia. Although neutrophils are key players in the pathophysiology of ischemic injuries, neither the dysregulation presented by these cells in iIRI nor the protective effect of iIPC have their regulation mechanisms fully understood. Protein phosphorylation, as well as the regulation of the respective phosphatases and kinases are responsible for regulating a large number of cellular functions in the inflammatory response. Moreover, in previous work we found hydrolases and transferases to be modulated in iIR and iIPC, suggesting the possible involvement of phosphatases and kinases in the process. Therefore, in the present study, we analyzed the phosphoproteome of neutrophils from rats submitted to mesenteric ischemia and reperfusion, either submitted or not to IPC, compared to quiescent controls and sham laparotomy. Proteomic analysis was performed by multi-step enrichment of phosphopeptides, isobaric labeling, and LC-MS/MS analysis. Bioinformatics was used to determine phosphosite and phosphopeptide abundance and clustering, as well as kinases and phosphatases sites and domains. We found that most of the phosphorylation-regulated proteins are involved in apoptosis and migration, and most of the regulatory kinases belong to CAMK and CMGC families. An interesting finding revealed groups of proteins that are modulated by iIR, but such modulation can be prevented by iIPC. Among the regulated proteins related to the iIPC protective effect, Vamp8 and Inpp5d/Ship are discussed as possible candidates for control of the iIR damage. Full article

(This article belongs to the Special Issue The Impact of Hypoxia on Neutrophil Signaling and Function)

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Review

Jump to: Research

21 pages, 1438 KiB

Open AccessReview

The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host

by Katharine M. Lodge, Andrew S. Cowburn, Wei Li and Alison M. Condliffe

Int. J. Mol. Sci. 2020, 21(4), 1183; https://doi.org/10.3390/ijms21041183 - 11 Feb 2020

Cited by 50 | Viewed by 7038

Abstract

Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of neutrophil extracellular traps; all of these microbicidal strategies require the deployment of cytotoxic proteins and proteases, packaged during neutrophil development within cytoplasmic granules. Neutrophils operate in infected and inflamed tissues, which can be profoundly hypoxic. Neutrophilic infiltration of hypoxic tissues characterises a myriad of acute and chronic infectious and inflammatory diseases, and as well as potentially protecting the host from pathogens, neutrophil granule products have been implicated in causing collateral tissue damage in these scenarios. This review discusses the evidence for the enhanced secretion of destructive neutrophil granule contents observed in hypoxic environments and the potential mechanisms for this heightened granule exocytosis, highlighting implications for the host. Understanding the dichotomy of the beneficial and detrimental consequences of neutrophil degranulation in hypoxic environments is crucial to inform potential neutrophil-directed therapeutics in order to limit persistent, excessive, or inappropriate inflammation. Full article

(This article belongs to the Special Issue The Impact of Hypoxia on Neutrophil Signaling and Function)

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23 pages, 1196 KiB

Open AccessReview

Neutrophil Metabolic Shift during Their Lifecycle: Impact on Their Survival and Activation

by Louise Injarabian, Anne Devin, Stéphane Ransac and Benoit S. Marteyn

Int. J. Mol. Sci. 2020, 21(1), 287; https://doi.org/10.3390/ijms21010287 - 31 Dec 2019

Cited by 74 | Viewed by 6791

Abstract

Polymorphonuclear neutrophils (PMNs) are innate immune cells, which represent 50% to 70% of the total circulating leukocytes. How PMNs adapt to various microenvironments encountered during their life cycle, from the bone marrow, to the blood plasma fraction, and to inflamed or infected tissues remains largely unexplored. Metabolic shifts have been reported in other immune cells such as macrophages or lymphocytes, in response to local changes in their microenvironment, and in association with a modulation of their pro-inflammatory or anti-inflammatory functions. The potential contribution of metabolic shifts in the modulation of neutrophil activation or survival is anticipated even though it is not yet fully described. If neutrophils are considered to be mainly glycolytic, the relative importance of alternative metabolic pathways, such as the pentose phosphate pathway, glutaminolysis, or the mitochondrial oxidative metabolism, has not been fully considered during activation. This statement may be explained by the lack of knowledge regarding the local availability of key metabolites such as glucose, glutamine, and substrates, such as oxygen from the bone marrow to inflamed tissues. As highlighted in this review, the link between specific metabolic pathways and neutrophil activation has been outlined in many reports. However, the impact of neutrophil activation on metabolic shifts’ induction has not yet been explored. Beyond its importance in neutrophil survival capacity in response to available metabolites, metabolic shifts may also contribute to neutrophil population heterogeneity reported in cancer (tumor-associated neutrophil) or auto-immune diseases (Low/High Density Neutrophils). This represents an active field of research. In conclusion, the characterization of neutrophil metabolic shifts is an emerging field that may provide important knowledge on neutrophil physiology and activation modulation. The related question of microenvironmental changes occurring during inflammation, to which neutrophils will respond to, will have to be addressed to fully appreciate the importance of neutrophil metabolic shifts in inflammatory diseases. Full article

(This article belongs to the Special Issue The Impact of Hypoxia on Neutrophil Signaling and Function)

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16 pages, 1532 KiB

Open AccessReview

The Impact of Hypoxia on the Host-Pathogen Interaction between Neutrophils and Staphylococcus aureus

by Natalia H Hajdamowicz, Rebecca C Hull, Simon J Foster and Alison M Condliffe

Int. J. Mol. Sci. 2019, 20(22), 5561; https://doi.org/10.3390/ijms20225561 - 7 Nov 2019

Cited by 26 | Viewed by 6114

Abstract

Neutrophils are key to host defence, and impaired neutrophil function predisposes to infection with an array of pathogens, with Staphylococcus aureus a common and sometimes life-threatening problem in this setting. Both infiltrating immune cells and replicating bacteria consume oxygen, contributing to the profound tissue hypoxia that characterises sites of infection. Hypoxia in turn has a dramatic effect on both neutrophil bactericidal function and the properties of S. aureus, including the production of virulence factors. Hypoxia thereby shapes the host–pathogen interaction and the progression of infection, for example promoting intracellular bacterial persistence, enabling local tissue destruction with the formation of an encaging abscess capsule, and facilitating the establishment and propagation of bacterial biofilms which block the access of host immune cells. Elucidating the molecular mechanisms underlying host–pathogen interactions in the setting of hypoxia will enable better understanding of persistent and recalcitrant infections due to S. aureus and may uncover novel therapeutic targets and strategies. Full article

(This article belongs to the Special Issue The Impact of Hypoxia on Neutrophil Signaling and Function)

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12 pages, 929 KiB

Open AccessReview

Hypoxic Regulation of Neutrophils in Cancer

by Daniel Triner and Yatrik M. Shah

Int. J. Mol. Sci. 2019, 20(17), 4189; https://doi.org/10.3390/ijms20174189 - 27 Aug 2019

Cited by 10 | Viewed by 3657

Abstract

Neutrophils have been well-characterized for their role in the host anti-microbial response. However, it is now appreciated that neutrophils have a critical role in tumorigenesis and tumor progression in the majority of solid tumors. Recent studies have indicated a critical role for hypoxia in regulating neutrophil function in tumors. Furthermore, neutrophil-specific expression of hypoxia-inducible transcription factors may represent a novel therapeutic target for human cancer. In this review, we highlight the function of neutrophils in cancer and the role of the neutrophil hypoxic response in regulating the neoplastic progression of cancer. Full article

(This article belongs to the Special Issue The Impact of Hypoxia on Neutrophil Signaling and Function)

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