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Physiological Reviews Apr 2019Neutrophils have always been considered as uncomplicated front-line troopers of the innate immune system equipped with limited proinflammatory duties. Yet recently, the... (Review)
Review
Neutrophils have always been considered as uncomplicated front-line troopers of the innate immune system equipped with limited proinflammatory duties. Yet recently, the role of the neutrophil has been undergoing a rejuvenation of sorts. Neutrophils are now considered complex cells capable of a significant array of specialized functions, and as an effector of the innate immune response, they are able to regulate many processes such as acute injury and repair, cancer, autoimmunity, and chronic inflammatory processes. Furthermore, evidence exists to indicate that neutrophils also contribute to adaptive immunity by aiding the development of specific adaptive immune responses or guiding the subsequent adaptive immune response. With this revived interest in neutrophils and their many novel functions, it is prudent to review what is currently known about neutrophils and, even more importantly, understand what information is lacking. We discuss the essential features of the neutrophil, from its origins, lifespan, subsets, margination and sequestration of the neutrophil to the death of the neutrophil. We highlight neutrophil recruitment to both infected and injured tissues and outline differences in recruitment of neutrophils between different tissues. Finally, we examine how neutrophils use different mechanisms to either bolster protective immune responses or negatively cause pathological outcomes at different locations.
Topics: Adaptive Immunity; Animals; Immunity, Innate; Infections; Inflammation; Neoplasms; Neutrophils
PubMed: 30758246
DOI: 10.1152/physrev.00012.2018 -
Blood May 2019Neutrophils act as the body's first line of defense against infection and respond to diverse inflammatory cues, including cancer. Neutrophils display plasticity, with... (Review)
Review
Neutrophils act as the body's first line of defense against infection and respond to diverse inflammatory cues, including cancer. Neutrophils display plasticity, with the ability to adapt their function in different inflammatory contexts. In the tumor microenvironment, neutrophils have varied functions and have been classified using different terms, including N1/N2 neutrophils, tumor-associated neutrophils, and polymorphonuclear neutrophil myeloid-derived suppressor cells (PMN-MDSCs). These populations of neutrophils are primarily defined by their functional phenotype, because few specific cell surface markers have been identified. In this review, we will discuss neutrophil polarization and plasticity and the function of proinflammatory/anti-inflammatory and protumor/antitumor neutrophils in the tumor microenvironment. We will also discuss how neutrophils with the ability to suppress T-cell activation, referred to by some as PMN-MDSCs, fit into this paradigm.
Topics: Animals; Humans; Inflammation; Lymphocyte Activation; Neoplasms; Neutrophils; Tumor Microenvironment
PubMed: 30898857
DOI: 10.1182/blood-2018-11-844548 -
Trends in Immunology Jul 2019New evidence has challenged the outdated dogma that neutrophils are a homogeneous population of short-lived cells. Although neutrophil subpopulations with distinct... (Review)
Review
New evidence has challenged the outdated dogma that neutrophils are a homogeneous population of short-lived cells. Although neutrophil subpopulations with distinct functions have been reported under homeostatic and pathological conditions, a full understanding of neutrophil heterogeneity and plasticity is currently lacking. We review here current knowledge of neutrophil heterogeneity and diversity, highlighting the need for deep genomic, phenotypic, and functional profiling of the identified neutrophil subpopulations to determine whether these cells truly represent bona fide novel neutrophil subsets. We suggest that progress in understanding neutrophil heterogeneity will allow the identification of clinically relevant neutrophil subpopulations that may be used in the diagnosis of specific diseases and lead to the development of new therapeutic approaches.
Topics: Animals; Biomarkers; Cell Plasticity; Disease Susceptibility; Female; Homeostasis; Humans; Immunity, Innate; Immunomodulation; Leukocyte Count; Neutrophils; Phenotype; Pregnancy
PubMed: 31160207
DOI: 10.1016/j.it.2019.04.012 -
Blood May 2019Neutrophils represent the first line of cellular defense against invading microorganism by rapidly moving across the blood-endothelial cell (EC) barrier and exerting... (Review)
Review
Neutrophils represent the first line of cellular defense against invading microorganism by rapidly moving across the blood-endothelial cell (EC) barrier and exerting effector cell functions. The neutrophil recruitment cascade to inflamed tissues involves elements of neutrophil rolling, firm adhesion, and crawling onto the EC surface before extravasating by breaching the EC barrier. The interaction between neutrophils and ECs occurs via various adhesive modules and is a critical event determining the mode of neutrophil transmigration, either at the EC junction (paracellular) or directly through the EC body (transcellular). Once thought to be a homogenous entity, new evidence clearly points to the plasticity of neutrophil functions. This review will focus on recent advances in our understanding of the mechanism of the neutrophil transmigration process. It will discuss how neutrophil-EC interactions and the subsequent mode of diapedesis, junctional or nonjunctional, can be context dependent and how this plasticity may be exploited clinically.
Topics: Animals; Cell Adhesion; Cell Communication; Endothelial Cells; Humans; Inflammation; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 30898863
DOI: 10.1182/blood-2018-12-844605 -
Frontiers in Immunology 2020Neutrophil Extracellular Traps (NETs) are net-like structures composed of DNA-histone complexes and proteins released by activated neutrophils. In addition to their key... (Review)
Review
Neutrophil Extracellular Traps (NETs) are net-like structures composed of DNA-histone complexes and proteins released by activated neutrophils. In addition to their key role in the neutrophil innate immune response, NETs are also involved in autoimmune diseases, like systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and in other non-infectious pathological processes, as coagulation disorders, thrombosis, diabetes, atherosclerosis, vasculitis, and cancer. Recently, a large body of evidence indicates that NETs are involved in cancer progression and metastatic dissemination, both in animal models and cancer patients. Interestingly, a close correlation between cancer cell recruitment of neutrophils in the tumor microenvironment (Tumor Associated Neutrophils. TANs) and NET formation has been also observed either in primary tumors and metastatic sites. Moreover, NETs can also catch circulating cancer cells and promote metastasis. Furthermore, it has been reported that wake dormant cancer cells, causing tumor relapse and metastasis. This review will primarily focus on the pro-tumorigenic activity of NETs in tumors highlighting their ability to serve as a potential target for cancer therapy.
Topics: Animals; Antineoplastic Agents; Disease Progression; Extracellular Traps; Humans; Immunotherapy; Neoplasm Metastasis; Neoplasms; Neutrophils; Signal Transduction; Tumor Microenvironment
PubMed: 33042107
DOI: 10.3389/fimmu.2020.01749 -
Biomolecules Aug 2019Neutrophil extracellular traps (NETs), a unique DNA framework decorated with antimicrobial peptides, have been in the scientific limelight for their role in a variety of... (Review)
Review
Neutrophil extracellular traps (NETs), a unique DNA framework decorated with antimicrobial peptides, have been in the scientific limelight for their role in a variety of pathologies ranging from cystic fibrosis to cancer. The formation of NETs, as well as relevant regulatory mechanisms, physiological factors, and pharmacological agents have not been systematically discussed in the context of their beneficial and pathological aspects. Novel forms of NET formation including vital NET formation continue to be uncovered, however, there remain fundamental questions around established mechanisms such as NADPH-oxidase (Nox)-dependent and Nox-independent NET formation. Whether NET formation takes place in the tissue versus the bloodstream, internal factors (e.g. reactive oxygen species (ROS) production and transcription factor activation), and external factors (e.g. alkaline pH and hypertonic conditions), have all been demonstrated to influence specific NET pathways. Elements of neutrophil biology such as transcription and mitochondria, which were previously of unknown significance, have been identified as critical mediators of NET formation through facilitating chromatin decondensation and generating ROS, respectively. While promising therapeutics inhibiting ROS, transcription, and gasdermin D are being investigated, neutrophil phagocytosis plays a critical role in host defense and any therapies targeting NET formation must avoid impairing the physiological functions of these cells. This review summarizes what is known in the many domains of NET research, highlights the most relevant challenges in the field, and inspires new questions that can bring us closer to a unified model of NET formation.
Topics: Animals; Extracellular Traps; Humans; Neutrophils; Reactive Oxygen Species
PubMed: 31416173
DOI: 10.3390/biom9080365 -
Cellular & Molecular Immunology May 2020Neutrophils are frontline cells of the innate immune system. These effector leukocytes are equipped with intriguing antimicrobial machinery and consequently display high... (Review)
Review
Neutrophils are frontline cells of the innate immune system. These effector leukocytes are equipped with intriguing antimicrobial machinery and consequently display high cytotoxic potential. Accurate neutrophil recruitment is essential to combat microbes and to restore homeostasis, for inflammation modulation and resolution, wound healing and tissue repair. After fulfilling the appropriate effector functions, however, dampening neutrophil activation and infiltration is crucial to prevent damage to the host. In humans, chemoattractant molecules can be categorized into four biochemical families, i.e., chemotactic lipids, formyl peptides, complement anaphylatoxins and chemokines. They are critically involved in the tight regulation of neutrophil bone marrow storage and egress and in spatial and temporal neutrophil trafficking between organs. Chemoattractants function by activating dedicated heptahelical G protein-coupled receptors (GPCRs). In addition, emerging evidence suggests an important role for atypical chemoattractant receptors (ACKRs) that do not couple to G proteins in fine-tuning neutrophil migratory and functional responses. The expression levels of chemoattractant receptors are dependent on the level of neutrophil maturation and state of activation, with a pivotal modulatory role for the (inflammatory) environment. Here, we provide an overview of chemoattractant receptors expressed by neutrophils in health and disease. Depending on the (patho)physiological context, specific chemoattractant receptors may be up- or downregulated on distinct neutrophil subsets with beneficial or detrimental consequences, thus opening new windows for the identification of disease biomarkers and potential drug targets.
Topics: Animals; Chemotactic Factors; Disease; Health; Humans; Neutrophils; Receptors, Formyl Peptide; Signal Transduction
PubMed: 32238918
DOI: 10.1038/s41423-020-0412-0 -
Nature Reviews. Immunology May 2016Neutrophil migration and its role during inflammation has been the focus of increased interest in the past decade. Advances in live imaging and the use of new model... (Review)
Review
Neutrophil migration and its role during inflammation has been the focus of increased interest in the past decade. Advances in live imaging and the use of new model systems have helped to uncover the behaviour of neutrophils in injured and infected tissues. Although neutrophils were considered to be short-lived effector cells that undergo apoptosis in damaged tissues, recent evidence suggests that neutrophil behaviour is more complex and, in some settings, neutrophils might leave sites of tissue injury and migrate back into the vasculature. The role of reverse migration and its contribution to resolution of inflammation remains unclear. In this Review, we discuss the different cues within tissues that mediate neutrophil forward and reverse migration in response to injury or infection and the implications of these mechanisms to human disease.
Topics: Animals; Chemotaxis, Leukocyte; Humans; Infections; Inflammation; Neutrophil Infiltration; Neutrophils; Signal Transduction; Wound Healing
PubMed: 27231052
DOI: 10.1038/nri.2016.49 -
Current Protocols in Immunology Aug 2015Neutrophils represent the first line of defense against bacterial and fungal pathogens. Indeed, patients with inherited and acquired qualitative and quantitative...
Neutrophils represent the first line of defense against bacterial and fungal pathogens. Indeed, patients with inherited and acquired qualitative and quantitative neutrophil defects are at high risk for developing bacterial and fungal infections and suffering adverse outcomes from these infections. Therefore, research aiming at defining the molecular factors that modulate neutrophil effector function under homeostatic conditions and during infection is essential for devising strategies to augment neutrophil function and improve the outcome of infected individuals. This unit describes a reproducible density gradient centrifugation-based protocol that can be applied in any laboratory to harvest large numbers of highly enriched and highly viable neutrophils from the bone marrow of mice both at the steady state and following infection with Candida albicans as described in UNIT. In another protocol, we also present a method that combines gentle enzymatic tissue digestion with a positive immunomagnetic selection technique or Fluorescence-activated cell sorting (FACS) to harvest highly pure and highly viable preparations of neutrophils directly from mouse tissues such as the kidney, the liver or the spleen. Finally, methods for isolating neutrophils from mouse peritoneal fluid and peripheral blood are included. Mouse neutrophils isolated by these protocols can be used for examining several aspects of cellular function ex vivo including pathogen binding, phagocytosis and killing, neutrophil chemotaxis, oxidative burst, degranulation and cytokine production, and for performing neutrophil adoptive transfer experiments.
Topics: Animals; Ascitic Fluid; Bone Marrow Cells; Cell Separation; Mice; Neutrophils
PubMed: 26237011
DOI: 10.1002/0471142735.im0320s110 -
Molecular Cancer Aug 2017Expression of high levels of immune cells including neutrophils has been associated with detrimental outcome in several solid tumors and new strategies to decrease their... (Review)
Review
Expression of high levels of immune cells including neutrophils has been associated with detrimental outcome in several solid tumors and new strategies to decrease their presence and activity are currently under clinical development. Here, we review some of the relevant literature of the role of neutrophils in different stages of the oncogenic process including tumor initiation, growth, proliferation or metastatic spreading and also focus on how neutrophil counts or the neutrophil-to-lymphocyte ratio may be used as a prognostic and predictive biomarker. Strategies to avoid the deleterious effects of neutrophils in cancer and to reduce their activity are discussed. Examples for such strategies include inhibition of CXCR1 and CXCR2 to decrease migration of neutrophils to tumoral areas or the inhibition of granulocyte colony stimulating factor to decrease the amount of neutrophils which has shown efficacy in preclinical models.
Topics: Humans; Leukocyte Count; Lymphocytes; Neoplasms; Neutrophils; Prognosis
PubMed: 28810877
DOI: 10.1186/s12943-017-0707-7