scholarly journals Olfactomedin 4 marks a subset of neutrophils in mice

2018 ◽  
Vol 25 (1) ◽  
pp. 22-33 ◽  
Author(s):  
Matthew N Alder ◽  
Jaya Mallela ◽  
Amy M Opoka ◽  
Patrick Lahni ◽  
David A Hildeman ◽  
...  
Keyword(s):  
Innate Immune System ◽  
Immune Cell ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Human Neutrophils ◽  
Null Mouse ◽  
Immune Functions ◽  
Single Population ◽  
Extracellular Traps ◽  
Neutrophil Differentiation

Neutrophils are the most abundant immune cell of the innate immune system and participate in essential immune functions. Heterogeneity within neutrophils has been documented, but it is difficult to distinguish if these are altered activation states of a single population or separate subpopulations of neutrophils determined at the time of differentiation. Several groups have identified a subset of human neutrophils that express olfactomedin 4 (OLFM4) and increased OLFM4+ neutrophils during sepsis is correlated with worse outcome, suggesting these neutrophils or the OLFM4 they secrete may be pathogenic. We tested if mice could be used as a model to study OLFM4+ neutrophils. We found the OLFM4 expressing subset of neutrophils is conserved in mice. Depending on the strain, 7–35% of murine neutrophils express OLFM4 and expression is determined early in neutrophil differentiation. OLFM4+ neutrophils phagocytose and transmigrate with similar efficiency as OLFM4− neutrophils. Here we show that within neutrophil extracellular traps (NETs) OLFM4+ and OLFM4− neutrophils undergo NETosis and OLFM4 colocalizes. Finally, we generated an OLFM4 null mouse and show that these mice are protected from death when challenged with sepsis, providing further evidence that the OLFM4 expressing subpopulation of neutrophils, or the OLFM4 they secrete, may be pathogenic during overwhelming infection.

scholarly journals Angiopoietin 1 release from human neutrophils is independent from neutrophil extracellular traps (NETs)

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Elcha Charles ◽  
Benjamin L. Dumont ◽  
Steven Bonneau ◽  
Paul-Eduard Neagoe ◽  
Louis Villeneuve ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Human Neutrophils ◽  
Extracellular Traps ◽  
Pathological Conditions ◽  
Healthy Control ◽  
Angiopoietin 1

Abstract Background Neutrophils induce the synthesis and release of angiopoietin 1 (Ang1), a cytosolic growth factor involved in angiogenesis and capable of inducing several pro-inflammatory activities in neutrophils. Neutrophils also synthesize and release neutrophil extracellular traps (NETs), comprised from decondensed nuclear DNA filaments carrying proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), proteinase 3 (PR3) and calprotectin (S100A8/S100A9), which together, contribute to the innate immune response against pathogens (e.g., bacteria). NETs are involved in various pathological conditions through pro-inflammatory, pro-thrombotic and endothelial dysfunction effects and have recently been found in heart failure (HF) and type 2 diabetes (T2DM) patients. The aim of the present study was to investigate the role of NETs on the synthesis and release of Ang1 by the neutrophils in patients with T2DM and HF with preserved ejection fraction (HFpEF) (stable or acute decompensated; ADHFpEF) with or without T2DM. Results Our data show that at basal level (PBS) and upon treatment with LPS, levels of NETs are slightly increased in patients suffering from T2DM, HFpEF ± T2DM and ADHF without (w/o) T2DM, whereas this increase was significant in ADHFpEF + T2DM patients compared to healthy control (HC) volunteers and ADHFpEF w/o T2DM. We also observed that treatments with PMA or A23187 increase the synthesis of Ang1 (from 150 to 250%) in HC and this effect is amplified in T2DM and in all cohorts of HF patients. Ang1 is completely released (100%) by neutrophils of all groups and does not bind to NETs as opposed to calprotectin. Conclusions Our study suggests that severely ill patients with HFpEF and diabetes synthesize and release a greater abundance of NETs while Ang1 exocytosis is independent of NETs synthesis.

scholarly journals Degraded neutrophil extracellular traps promote the growth of Actinobacillus pleuropneumoniae

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Nicole de Buhr ◽  
Marta C. Bonilla ◽  
Jessica Pfeiffer ◽  
Silke Akhdar ◽  
Cornelia Schwennen ◽  
...  
Keyword(s):  
Immune Cell ◽  
Bacterial Species ◽  
Severe Pneumonia ◽  
Lavage Fluid ◽  
Neutrophil Extracellular Traps ◽  
Actinobacillus Pleuropneumoniae ◽  
Degraded Dna ◽  
Human Neutrophils ◽  
Extracellular Traps

Abstract Actinobacillus pleuropneumoniae (A.pp) causes severe pneumonia associated with enormous economic loss in pigs. Peracute diseased pigs die in <24 h with pneumonia. Neutrophils are the prominent innate immune cell in this infection that massively infiltrate the infected lung. Here we show that neutrophils release neutrophil extracellular traps (NETs) as response to A.pp infection. Numerous NET-markers were identified in bronchoalveolar lavage fluid (BALF) of A.pp-infected piglets in vivo, however, most NET fibers are degraded. Importantly, A.pp is able to enhance its growth rate in the presence of NETs that have been degraded by nucleases efficiently. A.pp itself releases no nuclease, but we identified host nucleases as sources that degrade NETs after A.pp infection. Furthermore, the nucleases of co-infecting pathogens like Streptococcus suis increase growth of A.pp in presence of porcine NETs. Thus, A.pp is not only evading the antimicrobial activity of NETs, A.pp is rather additionally using parts of NETs as growth factor thereby taking advantage of host nucleases as DNase1 or nucleases of co-infecting bacteria, which degrade NETs. This effect can be diminished by inhibiting the bacterial adenosine synthase indicating that degraded NETs serve as a source for NAD, which is required by A.pp for its growth. A similar phenotype was found for the human pathogen Haemophilus (H.) influenzae and its growth in the presence of human neutrophils. H. influenzae benefits from host nucleases in the presence of neutrophils. These data shed light on the detrimental effects of NETs during host immune response against certain bacterial species that require and/or efficiently take advantage of degraded DNA material, which has been provided by host nuclease or nucleases of other co-infecting bacteria, as growth source.

scholarly journals Angiopoietin 1 release from Human Neutrophils is Independent from Neutrophil Extracellular Traps (NETs)

2021 ◽  
Author(s):  
Elcha Charles ◽  
Benjamin Dumont ◽  
Steven Bonneau ◽  
Paul-Eduard Neagoe ◽  
Louis Villeneuve ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Human Neutrophils ◽  
Extracellular Traps ◽  
Pathological Conditions ◽  
Healthy Control ◽  
Angiopoietin 1

Abstract Background: Neutrophils induce the synthesis and release of angiopoietin 1 (Ang1), a cytosolic growth factor involved in angiogenesis and capable of inducing several pro-inflammatory activities in neutrophils. Neutrophils also synthesize and release neutrophil extracellular traps (NETs), comprised from decondensed nuclear DNA filaments carrying proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), proteinase 3 (PR3) and calprotectin (S100A8/S100A9), which together, contribute to the innate immune response against pathogens (e.g., bacteria). NETs are involved in various pathological conditions through pro-inflammatory, pro-thrombotic and endothelial dysfunction effects and have recently been found in heart failure (HF) and type 2 diabetes (T2DM) patients. The aim of the present study was to investigate the role of NETs on the synthesis and release of Ang1 by the neutrophils in patients with T2DM and HF with preserved ejection fraction (HFpEF) (stable or acute decompensated; ADHFpEF) with or without T2DM. Results: Our data show that at basal level (PBS) and upon treatment with LPS, levels of NETs are slightly increased in patients suffering from T2DM, HFpEF ± T2DM and ADHF w/o T2DM, whereas this increase was significant in ADHFpEF + T2DM patients compared to healthy control (HC) volunteers and ADHFpEF without T2DM. We also observed that treatments with PMA or A23187 increase the synthesis of Ang1 (from 150 to 250%) in HC and this effect is amplified in T2DM and in all cohorts of HF patients. Ang1 is completely released (100%) by neutrophils of all groups and does not bind to NETs as opposed to calprotectin. Conclusions: Our study suggests that severely ill patients with HFpEF and diabetes synthesize and release a greater abundance of NETs while Ang1 exocytosis is independent of NETs synthesis.

scholarly journals Neutrophils and NETs in modulating acute and chronic inflammation

Blood ◽  
2019 ◽  
Vol 133 (20) ◽  
pp. 2178-2185 ◽  
Author(s):  
Fernanda V. S. Castanheira ◽  
Paul Kubes
Keyword(s):  
Chronic Inflammation ◽  
Host Defense ◽  
Innate Immune System ◽  
Tissue Repair ◽  
Essential Role ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Extracellular Traps ◽  
Acute And Chronic Inflammation

Abstract Neutrophils are an absolutely essential part of the innate immune system, playing an essential role in the control of infectious diseases but more recently are also being viewed as important players in tissue repair. Neutrophils are able to counteract an infection through phagocytosis and/or the release of neutrophil extracellular traps (NETs). By contrast, neutrophils help repair damaged tissues, limiting NET production but still phagocytosing debris. However, when inflammation is recurrent, or the inciting agent persists, neutrophils through a frustrated inability to resolve the problem can release NETs to exacerbate tissue damage during inappropriate inflammation. In this review, we discuss the mechanisms of NET formation, as well as the apparent paradoxical role of neutrophils and NETs in host defense, chronic inflammation, and tissue disrepair.

scholarly journals Neutrophil extracellular traps and their role in health and disease

2016 ◽  
Vol Volume 112 (Number 1/2) ◽  
Author(s):  
Jan G. Nel ◽  
Annette J. Theron ◽  
Roger Pool ◽  
Chrisna Durandt ◽  
Gregory R. Tintinger ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Neutrophil Extracellular Traps ◽  
Limited Range ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Alternative Mechanism ◽  
Viral Pathogens ◽  
Extracellular Traps ◽  
Health And Disease

Abstract The human innate immune system is indispensable for protection against potentially invasive microbial and viral pathogens, either neutralising them or containing their spread until effective mobilisation of the slower, adaptive (specific), immune response. Until fairly recently, it was believed that the human innate immune system possessed minimal discriminatory activity in the setting of a rather limited range of microbicidal or virucidal mechanisms. However, recent discoveries have revealed that the innate immune system possesses an array of novel pathogen recognition mechanisms, as well as a resourceful and effective alternative mechanism of phagocyte (predominantly neutrophil)-mediated, anti-infective activity known as NETosis. The process of NETosis involves an unusual type of programmed, purposeful cell death, resulting in the extracellular release of a web of chromatin heavily impregnated with antimicrobial proteins. These structures, known as neutrophil extracellular traps (NETs), immobilise and contribute to the eradication of microbial pathogens, ensuring that the anti-infective potential of neutrophils is sustained beyond the lifespan of these cells. The current review is focused on the mechanisms of NETosis and the role of this process in host defence. Other topics reviewed include the potential threats to human health posed by poorly controlled, excessive formation of NETs, specifically in relation to development of autoimmune and cardiovascular diseases, as well as exacerbation of acute and chronic inflammatory disorders of the airways.

scholarly journals The Dual Role of Myeloperoxidase in Immune Response

2020 ◽  
Vol 21 (21) ◽  
pp. 8057 ◽  
Author(s):  
Jürgen Arnhold
Keyword(s):  
Immune Response ◽  
Innate Immune System ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Major Constituent ◽  
Extracellular Traps ◽  
Atherosclerotic Lesions ◽  
Disease Specific ◽  
Frustrated Phagocytosis

The heme protein myeloperoxidase (MPO) is a major constituent of neutrophils. As a key mediator of the innate immune system, neutrophils are rapidly recruited to inflammatory sites, where they recognize, phagocytose, and inactivate foreign microorganisms. In the newly formed phagosomes, MPO is involved in the creation and maintenance of an alkaline milieu, which is optimal in combatting microbes. Myeloperoxidase is also a key component in neutrophil extracellular traps. These helpful properties are contrasted by the release of MPO and other neutrophil constituents from necrotic cells or as a result of frustrated phagocytosis. Although MPO is inactivated by the plasma protein ceruloplasmin, it can interact with negatively charged components of serum and the extracellular matrix. In cardiovascular diseases and many other disease scenarios, active MPO and MPO-modified targets are present in atherosclerotic lesions and other disease-specific locations. This implies an involvement of neutrophils, MPO, and other neutrophil products in pathogenesis mechanisms. This review critically reflects on the beneficial and harmful functions of MPO against the background of immune response.

scholarly journals Neutrophil Extracellular Traps in the Second Decade

2018 ◽  
Vol 10 (5-6) ◽  
pp. 414-421 ◽  
Author(s):  
Volker Brinkmann
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Pathophysiological Mechanisms ◽  
Extracellular Traps ◽  
Concise Overview ◽  
Health And Disease ◽  
The Right

Nearly 15 years after the first description of neutrophil extracellular traps (NETs), our knowledge concerning this structure has expanded considerably. Initially, NETs were considered solely an elaborate function of the innate immune system to combat invading microorganisms. Successively it became clear that NETs have farther-reaching capabilities. They are involved in a series of pathophysiological mechanisms ranging from inflammation to thrombosis where they fulfill essential functions when produced at the right site and the right time but can have a serious impact when generation or clearance of NETs is inadequately controlled. This review provides a concise overview on the far-reaching functions of NETs in health and disease.

Inhibition of PAD4 mediated neutrophil extracellular traps prevents fibrotic osseointegration failure in a tibial implant murine model

2021 ◽  
Vol 103-B (7 Supple B) ◽  
pp. 135-144
Author(s):  
Emile-Victor Kuyl ◽  
Fei Shu ◽  
Branden R. Sosa ◽  
Juan D. Lopez ◽  
Di Qin ◽  
...  
Keyword(s):  
Aseptic Loosening ◽  
Murine Model ◽  
Innate Immune System ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Bone Implant ◽  
Extracellular Traps ◽  
Fibrotic Tissue ◽  
Dnase 1 ◽  
Biological Target

Aims Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system’s response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through Pad4-/- mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue. Methods Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited ( Pad4-/- mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure. Results NETs biomarkers were identified in peri-implant fibrotic tissue collected from aseptic loosening patients and at the bone-implant interface in a murine model of osseointegration failure. Inhibition ( Pad4-/- ) or resolution (DNase 1) of NETs improved osseointegration and reduced fibrotic tissue despite loose implant conditions in mice. Conclusion This study identifies a biological target (NETs) for potential noninvasive treatments of aseptic loosening by discovering a novel connection between the innate immune system and post-injury bone remodelling caused by implant loosening. By inhibiting or resolving NETs in an osseointegration failure murine model, fibrotic tissue encapsulation around an implant is reduced and osseointegration is enhanced, despite loose implant conditions. Cite this article: Bone Joint J 2021;103-B(7 Supple B):135–144.

scholarly journals Role of Neutrophils on the Ocular Surface

2021 ◽  
Vol 22 (19) ◽  
pp. 10386
Author(s):  
Yongseok Mun ◽  
Jin Sun Hwang ◽  
Young Joo Shin
Keyword(s):  
Ocular Surface ◽  
Innate Immune System ◽  
Neutrophil Infiltration ◽  
Neutrophil Extracellular Traps ◽  
Therapeutic Agents ◽  
Innate Immune ◽  
Neutrophil Extracellular Trap ◽  
Extracellular Traps ◽  
Ocular Surface Diseases

The ocular surface is a gateway that contacts the outside and receives stimulation from the outside. The corneal innate immune system is composed of many types of cells, including epithelial cells, fibroblasts, natural killer cells, macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, mucin, and lysozyme. Neutrophil infiltration and degranulation occur on the ocular surface. Degranulation, neutrophil extracellular traps formation, called NETosis, and autophagy in neutrophils are involved in the pathogenesis of ocular surface diseases. It is necessary to understand the role of neutrophils on the ocular surface. Furthermore, there is a need for research on therapeutic agents targeting neutrophils and neutrophil extracellular trap formation for ocular surface diseases.

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