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Forlow, S. Bradley, Jill R. Schurr, Jay K. Kolls, Gregory J. Bagby, Paul O. Schwarzenberger y Klaus Ley. "Increased granulopoiesis through interleukin-17 and granulocyte colony-stimulating factor in leukocyte adhesion molecule–deficient mice". Blood 98, n.º 12 (1 de diciembre de 2001): 3309–14. http://dx.doi.org/10.1182/blood.v98.12.3309.
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Abstract Many mutant mice deficient in leukocyte adhesion molecules display altered hematopoiesis and neutrophilia. This study investigated whether peripheral blood neutrophil concentrations in these mice are elevated as a result of accumulation of neutrophils in the circulation or altered hematopoiesis mediated by a disrupted regulatory feedback loop. Chimeric mice were generated by transplanting various ratios of CD18+/+ and CD18−/− unfractionated bone marrow cells into lethally irradiated wild-type mice, resulting in approximately 0%, 10%, 50%, 90%, or 100% CD18 null neutrophils in the blood. The presence of only 10% CD18+/+ neutrophils was sufficient to prevent the severe neutrophilia seen in mice reconstituted with CD18−/− bone marrow cells. These data show that the neutrophilia in CD18−/− mice is not caused by enhanced neutrophil survival or the inability of neutrophils to leave the vascular compartment. In CD18−/−, CD18−/−E−/−, CD18−/−P−/−, EP−/−, and EPI−/− mice, levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-17 (IL-17) were elevated in proportion to the neutrophilia seen in these mice, regardless of the underlying mutation. Antibiotic treatment or the propensity to develop skin lesions did not correlate with neutrophil counts. Blocking IL-17 or G-CSF function in vivo significantly reduced neutrophil counts in severely neutrophilic mice by approximately 50% (P < .05) or 70% (P < .01), respectively. These data show that peripheral blood neutrophil numbers are regulated by a feedback loop involving G-CSF and IL-17 and that this feedback loop is disrupted when neutrophils cannot migrate into peripheral tissues.
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McGovern, Toby K., Michael Chen, Benoit Allard, Kjell Larsson, James G. Martin y Mikael Adner. "Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness". American Journal of Physiology-Lung Cellular and Molecular Physiology 310, n.º 2 (15 de enero de 2016): L155—L165. http://dx.doi.org/10.1152/ajplung.00172.2015.
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Airway exposure to organic dust (OD) from swine confinement facilities induces airway inflammation dominated by neutrophils and airway hyperresponsiveness (AHR). One important neutrophilic innate defense mechanism is the induction of oxidative stress. Therefore, we hypothesized that neutrophils exacerbate airway dysfunction following OD exposure by increasing oxidant burden. BALB/C mice were given intranasal challenges with OD or PBS (1/day for 3 days). Mice were untreated or treated with a neutrophil-depleting antibody, anti-Ly6G, or the antioxidant dimethylthiourea (DMTU) prior to OD exposure. Twenty-four hours after the final exposure, we measured airway responsiveness in response to methacholine (MCh) and collected bronchoalveolar lavage fluid to assess pulmonary inflammation and total antioxidant capacity. Lung tissue was harvested to examine the effect of OD-induced antioxidant gene expression and the effect of anti-Ly6G or DMTU. OD exposure induced a dose-dependent increase of airway responsiveness, a neutrophilic pulmonary inflammation, and secretion of keratinocyte cytokine. Depletion of neutrophils reduced OD-induced AHR. DMTU prevented pulmonary inflammation involving macrophages and neutrophils. Neutrophil depletion and DMTU were highly effective in preventing OD-induced AHR affecting large, conducting airways and tissue elastance. OD induced an increase in total antioxidant capacity and mRNA levels of NRF-2-dependent antioxidant genes, effects that are prevented by administration of DMTU and neutrophil depletion. We conclude that an increase in oxidative stress and neutrophilia is critical in the induction of OD-induced AHR. Prevention of oxidative stress diminishes neutrophil influx and AHR, suggesting that mechanisms driving OD-induced AHR may be dependent on neutrophil-mediated oxidant pathways.
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Yamasaki, Akira, Ryota Okazaki y Tomoya Harada. "Neutrophils and Asthma". Diagnostics 12, n.º 5 (8 de mayo de 2022): 1175. http://dx.doi.org/10.3390/diagnostics12051175.
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Although eosinophilic inflammation is characteristic of asthma pathogenesis, neutrophilic inflammation is also marked, and eosinophils and neutrophils can coexist in some cases. Based on the proportion of sputum cell differentiation, asthma is classified into eosinophilic asthma, neutrophilic asthma, neutrophilic and eosinophilic asthma, and paucigranulocytic asthma. Classification by bronchoalveolar lavage is also performed. Eosinophilic asthma accounts for most severe asthma cases, but neutrophilic asthma or a mixture of the two types can also present a severe phenotype. Biomarkers for the diagnosis of neutrophilic asthma include sputum neutrophils, blood neutrophils, chitinase-3-like protein, and hydrogen sulfide in sputum and serum. Thymic stromal lymphoprotein (TSLP)/T-helper 17 pathways, bacterial colonization/microbiome, neutrophil extracellular traps, and activation of nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 pathways are involved in the pathophysiology of neutrophilic asthma and coexistence of obesity, gastroesophageal reflux disease, and habitual cigarette smoking have been associated with its pathogenesis. Thus, targeting neutrophilic asthma is important. Smoking cessation, neutrophil-targeting treatments, and biologics have been tested as treatments for severe asthma, but most clinical studies have not focused on neutrophilic asthma. Phosphodiesterase inhibitors, anti-TSLP antibodies, azithromycin, and anti-cholinergic agents are promising drugs for neutrophilic asthma. However, clinical research targeting neutrophilic inflammation is required to elucidate the optimal treatment.
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Mizgerd, J. P., B. B. Meek, G. J. Kutkoski, D. C. Bullard, A. L. Beaudet y C. M. Doerschuk. "Selectins and neutrophil traffic: margination and Streptococcus pneumoniae-induced emigration in murine lungs." Journal of Experimental Medicine 184, n.º 2 (1 de agosto de 1996): 639–45. http://dx.doi.org/10.1084/jem.184.2.639.
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The roles of selectins in the pulmonary margination and emigration of neutrophils were investigated by using mice genetically deficient in both E- and P-selectins (E/P mutants) and/or by intravenous injections of fucoidin (inhibiting both L- and P-selectins). E/P mutants were neutrophilic (14.7 +/- 4.9 x 10(6) vs. 0.8 +/- 0.1 x 10(6) neutrophils/ml). This neutrophilia was associated with increased margination of neutrophils within pulmonary capillaries (39.7 +/- 9.4 vs. 4.6 +/- 1.1 neutrophil profiles per 100 red blood cell profiles) but no change in margination within noncapillary pulmonary microvessels. After intratracheal instillation of Streptococcus pneumoniae, lungs of E/P mutants displayed increased neutrophil emigration (564 +/- 92 vs. 116 +/- 19 neutrophils per 100 alveolar profiles), edema (5.3 +/- 1.5 vs. 1.5 +/- 0.4 microliter/g body weight), and histologic evidence of lung injury compared with those in wild-type (WT). Fucoidin treatment did not affect neutrophil emigration during streptococcal pneumonia in WT or E/P mice. During pneumonia, the number of white blood cells (WBC) tethered to or spread upon the noncapillary vessel endothelium increased in both WT and E/P lungs. These are the first data demonstrating that neutrophil margination in uninfected pulmonary capillaries does not require E- and P-selectins; that streptococcal pneumonia induces an E- and P-selectin-independent increase in WBC interactions with noncapillary endothelium; and that migration of neutrophils to alveoli can occur despite deficiency or inhibition of all of the known selectins.
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Weinmann, Pamela, Karin Scharffetter-Kochanek, S. Bradley Forlow, Thorsten Peters y Barbara Walzog. "A role for apoptosis in the control of neutrophil homeostasis in the circulation: insights from CD18-deficient mice". Blood 101, n.º 2 (15 de enero de 2003): 739–46. http://dx.doi.org/10.1182/blood-2002-01-0239.
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The control of neutrophil turnover in the circulation is a key event in homeostasis and inflammation. Using CD18- deficient (CD18−/−) mice that show a 19-fold increase of blood neutrophil counts when compared with wild-type animals (CD18+/+), we found that apoptosis of peripheral neutrophils was significantly reduced from 27.4% in the wild-type to 4.8% inCD18−/− mice within 4 hours after isolation as measured by analysis of DNA content. This was confirmed by detecting CD16 expression, nuclear morphology, and internucleosomal DNA degradation. In contrast, no difference in apoptosis was observed in neutrophils derived from the bone marrow. Neutrophilia and delayed neutrophil apoptosis were also present inCD18−/−/interleukin 6 (IL-6−/−) double knockout mice. Moreover, plasma ofCD18−/− mice was not able to delay apoptosis of CD18+/+neutrophils and plasma ofCD18+/+ mice did not augment apoptosis of CD18−/−neutrophils. However,CD18−/− neutrophils revealed an up-regulation of the antiapoptotic gene bcl-Xl and a down-regulation of the proapoptotic gene bax-α compared withCD18+/+ neutrophils suggesting that this delayed apoptosis. Accordingly, down-regulation of Bax-α using antisense technique delayed apoptosis and prolonged neutrophil survival. The replacement of the hematopoietic system of CD18+/+ mice by a 1:1 mixture of CD18+/+ andCD18−/− hematopoietic cells abolished the delay of apoptosis in peripheralCD18−/− neutrophils and prevented neutrophilia. Altogether, this suggests that a delay of neutrophil apoptosis inCD18−/− mice causes an alteration of neutrophil homeostasis, which may induce the massive increase of peripheral neutrophil counts. Thus, apoptosis seems to be critically involved in the control of neutrophil turnover in the circulation.
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Borges, Leandro, Tania Cristina Pithon-Curi, Rui Curi y Elaine Hatanaka. "COVID-19 and Neutrophils: The Relationship between Hyperinflammation and Neutrophil Extracellular Traps". Mediators of Inflammation 2020 (2 de diciembre de 2020): 1–7. http://dx.doi.org/10.1155/2020/8829674.
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Coronavirus disease 2019 (COVID-19) is a virus-induced respiratory disease that may progress to acute respiratory distress syndrome (ARDS) and is triggered by immunopathological mechanisms that cause excessive inflammation and leukocyte dysfunction. Neutrophils play a critical function in the clearance of bacteria with specific mechanisms to combat viruses. The aim of this review is to highlight the current advances in the pathways of neutrophilic inflammation against viral infection over the past ten years, focusing on the production of neutrophil extracellular traps (NETs) and its impact on severe lung diseases, such as COVID-19. We focused on studies regarding hyperinflammation, cytokine storms, neutrophil function, and viral infections. We discuss how the neutrophil’s role could influence COVID-19 symptoms in the interaction between hyperinflammation (overproduction of NETs and cytokines) and the clearance function of neutrophils to eliminate the viral infection. We also propose a more in-depth investigation into the neutrophil response mechanism targeting NETosis in the different phases of COVID-19.
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Wang, Guoshun y Hang Pong Ng. "Myeloid CFTR Loss-of-function Causes Persistent Neutrophilic Inflammation in Cystic Fibrosis". Journal of Immunology 202, n.º 1_Supplement (1 de mayo de 2019): 187.33. http://dx.doi.org/10.4049/jimmunol.202.supp.187.33.
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Abstract Persistent neutrophilic inflammation is a hallmark manifestation of cystic fibrosis (CF). However, the mechanism underlying this phenomenal clinical symptom remains incompletely understood. Here we report a pivotal role of CFTR in myeloid immune cells in control of neutrophilic inflammation. Myeloid CFTR-Knockout (Mye-Cftr−/−) mice and Wild-type (WT) mice were challenged peritoneally with zymosan at different doses. The lethal-dose challenge resulted in significantly higher mortality in Mye-Cftr−/− mice, indicating an intrinsic defect in host protection against inflammation in CF. The sub-lethal-dose challenge demonstrated an impaired resolution of inflammation in Mye-Cftr−/− mice, reflected by persistent neutrophilic inflammation, and hyper-inflammation with significantly higher levels of pro-inflammatory cytokines, including the neutrophil-recruiting chemokines MIP-2 and KC, which led to excessive neutrophil recruitment in vivo. Pulmonary challenge with zymosan confirmed the peritoneal finding. To determine the major types of cells responsible for the over-recruitment of neutrophils, zymosan-elicited peritoneal neutrophils and macrophages from Mye-Cftr−/− and WT mice were FACS-sorted and cultured ex vivo. The CF neutrophils produced significantly more neutrophil chemokine MIP-2. Moreover, peripheral blood neutrophils and monocytes from Mye-Cftr−/− and WT mice were cultured and stimulated with zymosan in vitro. Similarly, the CF neutrophils produced significantly more MIP-2. These data altogether suggest that CFTR dysfunction in myeloid immune cells leads to excessive neutrophil recruitment, thus serving as a mechanism for the long-observed neutrophilic inflammation in CF.
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Tomar, Bhawna, Hans-Joachim Anders, Jyaysi Desai y Shrikant R. Mulay. "Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19". Cells 9, n.º 6 (2 de junio de 2020): 1383. http://dx.doi.org/10.3390/cells9061383.
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The COVID-19 pandemic is progressing worldwide with an alarming death toll. There is an urgent need for novel therapeutic strategies to combat potentially fatal complications. Distinctive clinical features of severe COVID-19 include acute respiratory distress syndrome, neutrophilia, and cytokine storm, along with severe inflammatory response syndrome or sepsis. Here, we propose the putative role of enhanced neutrophil infiltration and the release of neutrophil extracellular traps, complement activation and vascular thrombosis during necroinflammation in COVID-19. Furthermore, we discuss how neutrophilic inflammation contributes to the higher mortality of COVID-19 in patients with underlying co-morbidities such as diabetes and cardiovascular diseases. This perspective highlights neutrophils as a putative target for the immunopathologic complications of severely ill COVID-19 patients. Development of the novel therapeutic strategies targeting neutrophils may help reduce the overall disease fatality rate of COVID-19.
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Inauen, W., D. N. Granger, C. J. Meininger, M. E. Schelling, H. J. Granger y P. R. Kvietys. "Anoxia-reoxygenation-induced, neutrophil-mediated endothelial cell injury: role of elastase". American Journal of Physiology-Heart and Circulatory Physiology 259, n.º 3 (1 de septiembre de 1990): H925—H931. http://dx.doi.org/10.1152/ajpheart.1990.259.3.h925.
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The aim of this study was to assess the role of neutrophilic elastase in anoxia-reoxygenation-induced, neutrophil-mediated injury to microvascular endothelium. Cultured bovine microvascular endothelial cells were grown to confluence and labeled with 51Cr. The endothelial cells were exposed to a 30-min period of anoxia and subsequently reoxygenated. Endothelial cell injury, quantitated as 51Cr release and cell detachment, was determined 8 h after reoxygenation. Addition of neutrophils upon reoxygenation enhanced the anoxia-reoxygenation-induced increase in 51Cr release and cell detachment. The neutrophil-mediated injury was associated with elastase release from the neutrophils. Four agents were used to inhibit neutrophilic elastase activity: Eglin C, methoxysuccunyl-Ala2-Pro-Val-CH2Cl, L658,758, and a monoclonal antibody against neutrophilic elastase. All elastase inhibitors attenuated the neutrophil-mediated endothelial cell detachment but not 51Cr release. Addition of purified human neutrophilic elastase, at a level that mimicked the release from neutrophils, increased cell detachment in endothelial cells exposed to anoxia-reoxygenation but did not affect 51Cr release. Our results indicate that elastase plays an important role in anoxia-reoxygenation-induced, neutrophil-mediated endothelial cell dysfunction.
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Gadjeva, Mihaela, Abirami Kugadas, Anastasia Petenkova, Jennifer Geddes-McAlister, Michael K. Mansour y David Sykes. "Neutrophil maturation and their response to infectious pathogens are regulated by microbiota". Journal of Immunology 202, n.º 1_Supplement (1 de mayo de 2019): 127.22. http://dx.doi.org/10.4049/jimmunol.202.supp.127.22.
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Abstract It has long been considered that a neutrophil’s response to various infectious challenges is innately pre-determined. Here, we provide data that demonstrates that neutrophil proteomes are modulated by the microbiota. We found that the proteomic signatures of mature neutrophils derived from germ free (GF) and specific pathogen free (SPF) mice were significantly different. In the absence of microbiota, mature neutrophils lacked GM-CSF-driven priming. To identify molecular pathways, we set-up an in vitro system where neutrophil progenitors were transduced with lenti-guides to knock-down key microbiota-driven pathway gene targets. GF-serum exposed neutrophil progenitors did not mature efficiently and had compromised bactericidal properties when compared to progenitors matured in SPF-derived serum. To identify which of the microbiota-driven proteins directly impacted bactericidal functions of neutrophils, we knocked out 19 candidates and tested their killing efficacy. Among all tested clones, one demonstrated a superior inhibition of neutrophil’s bactericidal capacities. Excitingly, this protein had no previously identified function: the knock down of prenylcysteine oxidase-like 1 (pcyox 1l) protein reduced neutrophil’s ability to kill efficiently P. aeruginosa in vitro due to diminished ROS release. Hence, we identified a novel mechanism for microbiota-driven control of innate immunity. Cumulatively, the data support the concept that microbiota affects neutrophil maturation by defining not only the quantity, but also the quality of mature neutrophils. We predict that neutrophil responses can be specifically tailored to pathogens.
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Wang, Jun-Xia y Peter Nigrovic. "CD177 participates in a novel mechanism for regulating neutrophil recruitment (P3093)". Journal of Immunology 190, n.º 1_Supplement (1 de mayo de 2013): 43.9. http://dx.doi.org/10.4049/jimmunol.190.supp.43.9.
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Abstract Background: Neutrophils are the sine qua non of inflammatory arthritis, and contribute to pain, swelling, and tissue injury, rendering neutrophil migration to the joint a potential therapeutic target. We recently found that the murine neutrophil surface protein Ly6G modulates chemotaxis via interaction with β2 integrins. Whereas CD177 is a neutrophil-specific human protein in the same gene family, we sought to identify the role of CD177 in human neutrophil recruitment. Method: Flow cytometry was used to analyze the levels of cell surface proteins in circulating neutrophils and in neutrophils from inflamed joints. Fluorescence lifetime imaging microscopy/Fluorescence resonance energy transfer assay (FLIM/FRET) was used to quantify CD177-β2 integrin interactions. Result: In patients with rheumatoid arthritis, synovial neutrophils exhibit higher levels of surface CD177 expression comparing with blood neutrophils. Using FLIM/FRET, ~40% CD11a and ~20% CD11b β2 integrins interact with CD177 on surface of resting blood neutrophils. In vitro, a specific CD177 antibody inhibits LTB4-induced conformational activation of CD11b β2 integrin, which is correlated with an impaired neutrophil migration towards LTB4 in anti-CD177 treated cells in a transwell system. Conclusion: CD177 regulates neutrophil chemotaxis and may serve as a potential neutrophil-specific therapeutic target in neutrophilic inflammatory diseases such as arthritis.
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Teske, Sabine, Andrea A. Bohn, Jean F. Regal, Joshua J. Neumiller y B. Paige Lawrence. "Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus". American Journal of Physiology-Lung Cellular and Molecular Physiology 289, n.º 1 (julio de 2005): L111—L124. http://dx.doi.org/10.1152/ajplung.00318.2004.
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Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1α, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12–24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.
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Grisham, M. B., J. Everse y H. F. Janssen. "Endotoxemia and neutrophil activation in vivo". American Journal of Physiology-Heart and Circulatory Physiology 254, n.º 5 (1 de mayo de 1988): H1017—H1022. http://dx.doi.org/10.1152/ajpheart.1988.254.5.h1017.
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There is a growing body of data to suggest that marginated granulocytes mediate much of the pulmonary damage observed during endotoxemia. The mechanism(s) by which endotoxemia initiates neutrophil margination and cytotoxicity remain either controversial or unknown. The objectives of this study were 1) to determine the temporal relationship between endotoxin-induced decreases in mean arterial pressure and circulating neutrophils, 2) to monitor neutrophil activation in vivo by measuring myeloperoxidase (MPO) activity in the plasma and lymph, and 3) to assess the interaction between endotoxin and complement in activation of neutrophilic oxidative metabolism in vitro. We found that a bolus injection of endotoxin causes a concurrent decrease in both mean arterial pressure and circulating neutrophils at 2 min postinfusion. Blood pressure recovered to approximately 70% of control values by 180 min, whereas circulating neutrophils remain depressed at 20% of control values for the entire experimental period. Using MPO as a marker for neutrophil activation, we found that infusion of endotoxin produces a dramatic increase in plasma and lymph MPO activity, suggesting activation of neutrophilic metabolism in vivo. In vitro data showed that both endotoxin and plasma were required for optimal neutrophilic degranulation and superoxide formation. We conclude that 1) the appearance of MPO in the plasma (or lymph) may be a useful neutrophil marker for neutrophil activation in vivo and may prove useful in following the course of neutrophil-mediated tissue injury during endotoxemia, and 2) endotoxin-activated complement (C5a) activates neutrophils to produce cytotoxic oxidants.
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Mariscalco, M. Michele, M. Hossein Tcharmtchi y C. Wayne Smith. "P-Selectin Support of Neonatal Neutrophil Adherence Under Flow: Contribution of L-Selectin, LFA-1, and Ligand(s) for P-Selectin". Blood 91, n.º 12 (15 de junio de 1998): 4776–85. http://dx.doi.org/10.1182/blood.v91.12.4776.
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Abstract To further define the neonatal neutrophil's ability to localize to inflamed tissue compared with adult cells, we examined the neonatal neutrophil interactions with P-selectin monolayers under two conditions: (1) attachment under constant shear stress and flow and (2) detachment where cells were allowed to attach in the absence of shear stress and then shear stress is introduced and increased in step-wise increments. Cord blood and adult neutrophils had minimal interactions with unstimulated human umbilical vein endothelial cells (HUVECs) at a constant shear stress of 2 dynes/cm2. There was a marked increase in the number of both neonatal and adult cells interacting (interacting cells = rolling + arresting) with HUVECs after histamine stimulation, although the neonatal value was only 40% of adult (P < .05). Neonatal neutrophils also had significantly decreased interaction with monolayers of Chinese hamster ovary (CHO) cells transfected with human P-selectin (CHO-P-selectin; 60% of adult values, P < .003). Of the interacting cells, there was a lower fraction of neonatal cells that rolled compared with adult cells on both stimulated HUVECs and CHO-P-selectin. That neonatal neutrophil L-selectin contributes to the diminished attachment to P-selectin is supported by the following: (1) Neonatal neutrophils had significantly diminished expression of L-selectin. (2) Anti–L-selectin monoclonal antibody reduced the number of interacting adult neutrophils to the level seen with untreated neonatal neutrophils, but had no effect on neonatal neutrophils. In contrast, L-selectin appeared to play no role in maintaining the interaction of either neonatal or adult neutrophils in the detachment assay. Once attachment occurred, the neonatal neutrophil's interaction with the P-selectin monolayer was dependent on LFA-1 and to other ligands to a lesser degree based on the following: (1) Control neonatal neutrophils had decreased rolling fraction compared with adult neutrophils, although the total number of interacting neutrophils was equal between groups. (2) Anti–LFA-1 treatment resulted in an increase in the rolling fraction of both neonatal and adult neutrophils. However, whereas the number of interacting adult neutrophils remained unchanged, the number of neonatal neutrophils decreased with increased shear stress. We speculate that this increased detachment of neonatal cells is due to differences in neutrophil ligand(s) for P-selectin.
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Mariscalco, M. Michele, M. Hossein Tcharmtchi y C. Wayne Smith. "P-Selectin Support of Neonatal Neutrophil Adherence Under Flow: Contribution of L-Selectin, LFA-1, and Ligand(s) for P-Selectin". Blood 91, n.º 12 (15 de junio de 1998): 4776–85. http://dx.doi.org/10.1182/blood.v91.12.4776.412k32_4776_4785.
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To further define the neonatal neutrophil's ability to localize to inflamed tissue compared with adult cells, we examined the neonatal neutrophil interactions with P-selectin monolayers under two conditions: (1) attachment under constant shear stress and flow and (2) detachment where cells were allowed to attach in the absence of shear stress and then shear stress is introduced and increased in step-wise increments. Cord blood and adult neutrophils had minimal interactions with unstimulated human umbilical vein endothelial cells (HUVECs) at a constant shear stress of 2 dynes/cm2. There was a marked increase in the number of both neonatal and adult cells interacting (interacting cells = rolling + arresting) with HUVECs after histamine stimulation, although the neonatal value was only 40% of adult (P < .05). Neonatal neutrophils also had significantly decreased interaction with monolayers of Chinese hamster ovary (CHO) cells transfected with human P-selectin (CHO-P-selectin; 60% of adult values, P < .003). Of the interacting cells, there was a lower fraction of neonatal cells that rolled compared with adult cells on both stimulated HUVECs and CHO-P-selectin. That neonatal neutrophil L-selectin contributes to the diminished attachment to P-selectin is supported by the following: (1) Neonatal neutrophils had significantly diminished expression of L-selectin. (2) Anti–L-selectin monoclonal antibody reduced the number of interacting adult neutrophils to the level seen with untreated neonatal neutrophils, but had no effect on neonatal neutrophils. In contrast, L-selectin appeared to play no role in maintaining the interaction of either neonatal or adult neutrophils in the detachment assay. Once attachment occurred, the neonatal neutrophil's interaction with the P-selectin monolayer was dependent on LFA-1 and to other ligands to a lesser degree based on the following: (1) Control neonatal neutrophils had decreased rolling fraction compared with adult neutrophils, although the total number of interacting neutrophils was equal between groups. (2) Anti–LFA-1 treatment resulted in an increase in the rolling fraction of both neonatal and adult neutrophils. However, whereas the number of interacting adult neutrophils remained unchanged, the number of neonatal neutrophils decreased with increased shear stress. We speculate that this increased detachment of neonatal cells is due to differences in neutrophil ligand(s) for P-selectin.
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Cavallaro, Elena C., Kar-Kate Liang, Kevin D. Forsyth y Dani-Louise Dixon. "Neutrophil polarization in the airways of infants with bronchiolitis". Journal of Immunology 198, n.º 1_Supplement (1 de mayo de 2017): 55.30. http://dx.doi.org/10.4049/jimmunol.198.supp.55.30.
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Abstract Pulmonary neutrophilia is observed in pediatric patients with viral-induced bronchiolitis. Despite an alleviation in clinical symptoms, our findings suggest that airway neutrophil infiltration and activation does not appear to resolve by discharge in hospitalized infants. The recent identification of neutrophil plasticity and polarization into distinct phenotypic pro-inflammatory (N1) and immunosuppressive (N2) subsets provides an unexplored avenue for regulation of the neutrophilic inflammatory response in bronchiolitis. Admission nasopharyngeal aspirate (NPA) samples were assessed from twelve bronchiolitic infants presenting to Flinders Medical Centre, Adelaide, Australia in 2013. An overall strong positive correlation between N2 soluble mediator TGF-β1 and the percentage of neutrophils stained for N2 marker MMP-9 was observed; with no correlation observed between TGF-β1 and neutrophils positive for N1 marker ICAM-1. In 2015 and 2016, eleven bronchiolitic infants provided consecutive NPAs across hospitalization. In both cohorts, concentrations of active TGF-β1 detected were comparable to levels previously identified to significantly suppress neutrophil activity in vitro (>1 pg/mL). Temporal assessment of neutrophil polarization is underway. The detection of pre-established neutrophil polarizing mediators, and the correlation of these mediators with different neutrophilic subsets within NPAs indicates a potential N1/N2 paradigm occurring within the airways of bronchiolitic infants. Further investigation is merited, with analyses over disease trajectory and by disease severity required to assess biological significance.
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Teddleton, Hannah G., Javier J. Garza, Scott P. Greiner y Scott A. Bowdridge. "157 Effect of Sheep Breed on Neutrophil Chemotaxis toHaemonchus Contortus Larval Antigen". Journal of Animal Science 101, Supplement_1 (1 de mayo de 2023): 105. http://dx.doi.org/10.1093/jas/skad068.126.
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Abstract Parasite-resistant St. Croix sheep generate a potent neutrophilic response to larval stages of Haemonchus contortus. Protective neutrophil responses can be best characterized by increased neutrophil infiltration to the abomasum within the first 3 days of infection. These data indicate breed differences in neutrophil chemotaxis and response to H. contortus infection. The purpose of this study was to determine differences in neutrophil chemotaxis by H. contortus third-stage larval (L3) antigen (HcLA). Suffolk (SUF) and St. Croix (STC) neutrophils were isolated and applied to matrigel-coated clearview inserts, and placed into a reservoir containing H. contortus HcLA, Interleukin-8 (IL-8), or complete media. Neutrophil chemotaxis plates were incubated (37°C, 5% CO2) in an Incucyte S3 live cell imaging system for 24 hours, and measurements taken hourly. Neutrophils from STC migrated towards HcLA quicker than SUF neutrophils, and this migration occurred as early as 3 hours (10% and 4% respectively, P < 0.001). The difference in breed chemotaxis increased over time, where 28% of STC neutrophils migrated at 14 hours compared with 13% of SUF cells at the same time. By 24 hours, 37% of STC neutrophils migrated towards HcLA while the percentage of migrating SUF neutrophils remained the same (13%). Positive control for neutrophil chemotaxis was IL-8, and 37% of STC neutrophils achieved migration at 7 hours compared with 26% SUF neutrophils. By 24 hours, IL-8 induced neutrophil chemotaxis was similar in both breeds (STC 47%, SUF 41%). Taken together, these data indicate that delayed responses in neutrophil chemotaxis may contribute to H. contortus establishment in parasite-susceptible hosts. Thus, indicating that neutrophil response to H. contortus infection is a critical component to full host protective immunity.
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Nwakoby, Izuchukwu E., Krishna Reddy, Puja Patel, Neena Shah, Saroj Sharma, Madhu Bhaskaran, Nora Gibbons, Aditi A. Kapasi y Pravin C. Singhal. "Fas-Mediated Apoptosis of Neutrophils in Sera of Patients with Infection". Infection and Immunity 69, n.º 5 (1 de mayo de 2001): 3343–49. http://dx.doi.org/10.1128/iai.69.5.3343-3349.2001.
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ABSTRACT In the presence of infection, neutropenia is considered to be a marker of poor prognosis; conversely, neutrophilia may not be a determinant of a better prognosis. Since apoptotic neutrophils are compromised functionally, we evaluated the effect of infection on neutrophil apoptosis. The rate of apoptosis was greater for neutrophils isolated from patients with infection than for healthy controls.Escherichia coli did not directly modulate the rate of neutrophil apoptosis. However, sera from infected patients promoted (P < 0.001) neutrophil apoptosis. Interestingly, the sera of patients with different types of infection (gram negative, gram positive, or culture negative) exerted a more or less identical response on neutrophil apoptosis. Sera of infected patients showed a fivefold greater content of FasL compared to controls. Moreover, anti-FasL antibody partly attenuated the infected-serum-induced neutrophil apoptosis. In in vitro studies, E. coli enhanced monocyte FasL expression. Moreover, conditioned media prepared from activated macrophages from control mice showed enhanced apoptosis of human as well as mouse neutrophils. On the contrary, conditioned media prepared from activated macrophages isolated from FasL-deficient mice induced only a mild degree of neutrophil apoptosis. These results suggest that neutrophils in patients with infection undergo apoptosis at an accelerated rate. Infection not only promoted monocyte expression of FasL but also increased FasL content of the serum. Because the functional status of apoptotic cells is compromised, a significant number of neutrophils may not be participating in the body's defense. Since neutrophils play the most important role in innate immunity, their compromised status in the presence of infection may transfer the host defense burden from an innate response to acquired immunity. The present study provides some insight into the lack of correlation between neutrophilia and the outcome of infection.
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Machado, Isabel Daufenback, José Roberto Santin, Carine Cristiane Drewes, Cristiane Damas Gil, Sonia Maria Oliani, Mauro Perretti y Sandra Helena Poliselli Farsky. "Alterations in the profile of blood neutrophil membrane receptors caused by in vivo adrenocorticotrophic hormone actions". American Journal of Physiology-Endocrinology and Metabolism 307, n.º 9 (1 de noviembre de 2014): E754—E763. http://dx.doi.org/10.1152/ajpendo.00227.2014.
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Elevated levels of adrenocorticotrophic hormone (ACTH) mobilize granulocytes from bone marrow into the blood, although these neutrophils are refractory to a full migratory response into inflamed tissues. Here, we investigated the dependence of glucocorticoid receptor activation and glucocorticoid-regulated protein annexin A1 (ANXA1) on ACTH-induced neutrophilia and the phenotype of blood neutrophil after ACTH injection, focusing on adhesion molecule expressions and locomotion properties. ACTH injection (5 μg ip, 4 h) induced neutrophilia in wild-type (WT) mice and did not alter the elevated numbers of neutrophils in RU-38486 (RU)-pretreated or ANXA1−/− mice injected with ACTH. Neutrophils from WT ACTH-treated mice presented higher expression of Ly6G+ANXA1high, CD18high, CD62Lhigh, CD49high, CXCR4high, and formyl-peptide receptor 1 (FPR1low) than those observed in RU-pretreated or ANXA1−/− mice. The membrane phenotype of neutrophils collected from WT ACTH-treated mice was paralleled by elevated fractions of rolling and adherent leukocytes to the cremaster postcapillary venules together with impaired neutrophil migration into inflamed air pouches in vivo and in vitro reduced formyl-methionyl-leucyl-phenylalanine (fMLP) or stromal-derived factor-1 (SDF-1α)-induced chemotaxis. In an 18-h senescence protocol, neutrophils from WT ACTH-treated mice had a higher proportion of ANXAVlow/CXCR4low, and they were less phagocytosed by peritoneal macrophages. We conclude that alterations on HPA axis affect the pattern of membrane receptors in circulating neutrophils, which may lead to different neutrophil phenotypes in the blood. Moreover, ACTH actions render circulating neutrophils to a phenotype with early reactivity, such as in vivo leukocyte-endothelial interactions, but with impaired locomotion and clearance.
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Harvath, L., K. B. Yancey y S. I. Katz. "Selective inhibition of human neutrophil chemotaxis to N-formyl-methionyl-leucyl-phenylalanine by sulfones." Journal of Immunology 137, n.º 4 (15 de agosto de 1986): 1305–11. http://dx.doi.org/10.4049/jimmunol.137.4.1305.
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Abstract The therapeutic efficacy of the sulfones, dapsone, and sulfoxone in neutrophilic dermatoses may be related to the effects of these drugs on neutrophil function. Therefore we determined whether neutrophil chemotactic migration to various chemoattractants could be inhibited by sulfones in vitro. The chemotactic responses of human neutrophils from healthy donors were tested by using N-formyl-methionyl-leucyl-phenylalanine (F-met-leu-phe), purified human C5a, and leukocyte-derived chemotactic factor (LDCF). Therapeutic concentrations of sulfones selectively inhibited neutrophil chemotaxis to F-met-leu-phe, but did not affect neutrophil chemotaxis to LDCF or C5a. Inhibition of neutrophil chemotaxis to F-met-leu-phe was induced by both dapsone and sulfoxone at a concentration of 10 micrograms/ml without affecting random migration, and the inhibition was reversed by washing the neutrophils. When dapsone- and sulfoxone-treated neutrophils (100 micrograms/ml) were stimulated with F-met-leu-phe, neutrophil superoxide generation was not inhibited. Sulfapyridine (10 micrograms/ml) also selectively inhibited neutrophil chemotaxis to F-met-leu-phe; however, sulfamethoxazole and sulfisoxazole did not affect chemotaxis. The inhibitory effects of dapsone, sulfoxone, and sulfapyridine could not be demonstrated with granulocytes from rabbits or guinea pigs nor with human monocytes. Experiments with radiolabeled dapsone showed rapid, nonspecific, and reversible binding of dapsone to human neutrophils. These data suggest that a mechanism of action of sulfones in neutrophilic dermatoses may be a selective inhibition of neutrophil migration to as yet undefined chemoattractants in the skin.
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White, Mitchell R., Tesfaldet Tecle, Erika C. Crouch y Kevan L. Hartshorn. "Impact of neutrophils on antiviral activity of human bronchoalveolar lavage fluid". American Journal of Physiology-Lung Cellular and Molecular Physiology 293, n.º 5 (noviembre de 2007): L1293—L1299. http://dx.doi.org/10.1152/ajplung.00266.2007.
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Surfactant protein D (SP-D) and neutrophils participate in the early innate immune response to influenza A virus (IAV) infection. SP-D increases neutrophil uptake of IAV and modulates neutrophil respiratory burst responses to IAV; however, neutrophil proteases have been shown to degrade SP-D, and human neutrophil peptide defensins bind to SP-D and can cause precipitation of SP-D from bronchoalveolar lavage fluid (BALF). BALF has significant antiviral activity against IAV. We first added neutrophils to BALF during incubation with IAV. Addition of neutrophils to BALF caused significantly greater clearance of IAV from culture supernatants than from BALF alone, and this effect was significantly more pronounced when neutrophils were activated during incubation with the virus. In contrast, if activated neutrophils were incubated with BALF before addition of virus, they reduced antiviral activity of BALF. This effect correlated with depletion of SP-D from BALF. Activation of neutrophils with agonists that induce primary granule release (including release of human neutrophil peptide defensins) caused SP-D depletion, but activation with PMA, which causes only secondary granule release, did not. The ability of activated neutrophils to deplete SP-D from BALF was partially, but not fully, corrected with protease inhibitors but was unaffected by inhibition of neutrophil respiratory burst responses. These results suggest that chronic neutrophilic inflammation (e.g., as in chronic smoking or cystic fibrosis) may reduce SP-D levels and predispose to IAV infection. In contrast, acute inflammation, as occurs in the early phase of IAV infection, may promote neutrophil-mediated viral clearance.
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Albahrani, Khuzama, Jumanah Alessa, Baraa Falemban, Mayyadah Abdullah Alkuwayti y Jamal Hussen. "NETosis and Calcium influx in Dromedary Camel Neutrophils after in vitro Toll-like Receptor Stimulation". World's Veterinary Journal 13 (25 de marzo de 2023): 214–21. http://dx.doi.org/10.54203/scil.2023.wvj23.
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Neutrophilic granulocytes are vital immune cells of the early response to pathogens. They contribute to the antimicrobial response through phagocytosis, production of reactive oxygen species, cytokine production, degranulation, and NET-formation. Neutrophil extracellular traps (NETs), also known as NETosis, are a critical antibacterial effector mechanism of cells of myeloid effector cells, including neutrophils and macrophages. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that mediate pathogen sensing through the recognition of microbial structures known as pathogen-associated molecular patterns (PAMPs). The present study aimed to investigate the potential of several TLR ligands that mimic the sensing of bacterial and viral pathogens to stimulate NET-formation or Ca2+ influx in camel neutrophils. Neutrophils were purified from blood and were stimulated in vitro with ligands to TLR4, TLR2/1, TLR7/8, or TLR3. Net-formation was analyzed using the DNA-sensitive dye SYTOX™ Green and staining with antibodies to the neutrophil's granular enzyme myeloperoxidase. Real-time stimulation-induced Ca2+ influx was measured using the Ca2+-sensitive dye Flou-4 and flow cytometry. Only the TLR4-ligand lipopolysaccharide (LPS) could induce NET-formation in camel neutrophils, while none of the investigated TLR agonists showed a Ca2+ influx-inducing effect in camel neutrophils. The current study represents the first report on the impact of direct activation of TLR on NET-formation and Ca2+ influx in camel neutrophils with a selective effect of LPS on NET-formation induction. Future studies may investigate the molecular mechanisms behind the different responsiveness of bovine and camel neutrophils to TLR stimulation.
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Brinkworth, Jessica F., Kathrine Van Etten, Priya Bhatt, Keaton McClure, Negin Valizadegan, Minkyu Woo, Suvanthee Gunasekera, Yaravi Suarez y Brian Aldridge. "Functional comparison of human and non-human primate neutrophil responses". Journal of Immunology 202, n.º 1_Supplement (1 de mayo de 2019): 73.21. http://dx.doi.org/10.4049/jimmunol.202.supp.73.21.
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Abstract Humans and apes are neutrophilic, maintaining high levels (50–70% of circulating leukocytes) of this short-lived, highly reactive cell type (neutrophils), while most primates maintain significantly lower proportions(20–40% circulating leukocytes). Neutrophils are key limiters of bacterial and parasitic infection, amplifying inflammation, phagocytosing and presenting, and trapping invading foreign material, as well as committing bystander tissue damage in these efforts. The comparative neutrophilia of humans, therefore, suggests alterations in neutrophil activities such that higher proportions are both required and tolerated in this species. To address this possibility, we analyzed transcriptomic, and cell physiological responses of neutrophils from humans, and two biomedically important primates, rhesus macaque and common marmoset. Cells were isolated via a density gradient and stimulated with 1ng-1ug of lipopolysaccarhide (LPS) from Escherichia coli K12 or the bacteria itself (MOI 10:1) for 1–3 hours. Transcriptomic responses were captured by RNAseq, and physiological responses [phagocytosis, apoptosis, extracellular trapping (NETing)] by fluorescent microscopy. The species differed strongly the expression of genes in innate immune and cell trafficking pathways. Overall, primates exhibited NETing and apoptosis sensitivity to even the lowest dose of LPS. Humans, however, displayed a unique complement of neutrophil antimicrobial responses - phagocytosing and apoptosising more, while NETing less than the other species. These results suggest inter-species differences in important neutrophil antimicrobial strategies that may impact interpretation of primate biomedical models.
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Djimde, Moussa, Kassoum Kayentao, Japhet Kabalu Tshiongo, Bakary Fofana, Charles Arama, Sodiomon B. Sirima, Jean Bosco Ouedraogo et al. "Variation in neutrophil levels and artemisinin-based combination therapy efficacy in West-Africa". Journal of Infection in Developing Countries 17, n.º 09 (30 de septiembre de 2023): 1337–45. http://dx.doi.org/10.3855/jidc.17089.
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Introduction: Polymorphonuclear neutrophils (PMN) are involved in pathogen clearance by phagocytosis. However, the role of PMNs in the efficacy of artemisinin-based combination therapy (ACT) is poorly understood. Methodology: In a prospective longitudinal in vivo study, neutrophil rates were compared with malaria carriage after treatment with different ACTs: Artemether - lumefantrine (AL), Artesunate - amodiaquine (ASAQ), Dihydroartemisinin - piperaquine (DP) or Pyronaridine artesunate (PA). The study cases were classified as having neutropenia, normal neutrophil levels or neutrophilia depending on the level of neutrophils in the blood. This study included 3148 patients and was analyzed using R. Results: On day 7, only four patients in the neutropenia group and treated with AL had a malaria positive blood smear based on microscopy. On day 28, the rate of recurrent parasitemia in the AL arm was significantly higher in neutropenia patients (50.9%) than in patients with normal rates of neutrophils (43.1%) or in those with neutrophilia (6.0%) (p < 0.001). In ASAQ arm, the rate of recurrent Plasmodium falciparum parasitemia was 58.8% in the neutropenia group versus 29.4% in patients with normal rates of neutrophils and 11.8% in patients with neutrophilia (p < 0.001). No patient treated with DP with normal neutrophil counts or neutrophilia was carrying malaria parasites on day 28. Among the 15 patients with parasitemia on day 28 in the PA arm, 11 (73.33%) had neutropenia while 4 (26.67%) had a normal neutrophil count (p < 0.001). Conclusions: Patients with neutropenia had higher rates of recurrent P. falciparum parasitemia after ACT.
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Yamamoto, Gaku, Mahiru Kawano, Michiko Bun, Koutaro Shimura, Aska Toda, Koji Nakamura, Yasuto Kinose et al. "Abstract 5329: Ovarian cancer predisposes neutrophils to form neutrophil extracellular traps(NETs)". Cancer Research 84, n.º 6_Supplement (22 de marzo de 2024): 5329. http://dx.doi.org/10.1158/1538-7445.am2024-5329.
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Abstract Objective: Neutrophil extracellular trap (NETs) are neutrophil-derived extracellular DNA released in response to inflammation. In contrast to their primary host-defensive role, NETs have been recently reported to promote cancer progression. The aim of this study is to investigate the role of NETs in ovarian cancer progression. Method: The clinical data of ovarian cancer patients who underwent primary surgery at Osaka University Medical Hospital were retrospectively reviewed (n=340). The relationship between neutrophilia, peritoneal dissemination and prognosis were analyzed. Prior to initial treatment, peripheral blood was obtained from newly diagnosed ovarian cancer patients and examined for CBC and granulocyte-colony stimulating factor (G-CSF) concentration by ELISA. To evaluate NETs formation capacity, isolated neutrophils were stimulated with G-CSF and incubated in vitro to monitor NETs formation. The ascites was collected at the initial surgery and assessed for G-CSF concentration and for neutrophils population using flow cytometry. The omental tissues were pathologically examined for NETs using H&E-staining and immunostaining with anti-Citrullinated Histon3 (CitH3) antibody. To test NETs induction capacity, we treated human peripheral blood neutrophils with the conditioned media from 20 ovarian cancer cell lines and the serum from ovarian cancer patients. Then human ovarian cancer OVCAR8 cells were co-cultured with NETs to evaluate the effect of NETs on cancer cell adhesion. Results: Neutrophilia (neutrophils>7000/µl) was found in 39 patients (39/340,11.5%). Patients with neutrophilia were associated with advanced disease accompanied by peritoneal dissemination and compromised survival compared to patients without neutrophilia (5-year PFS 40.0 vs 59.9 %, p 0.0027). In these patients, serum G-CSF was upregulated. Neutrophils from ovarian cancer patients formed NETs significantly earlier than those from benign tumor patients. Ovarian cancer patients with neutrophilia showed elevated G-CSF concentration and increased neutrophils proportion in their ascites. Omental tissues from patients with neutrophilia showed NETs foci close to the disseminated lesions. G-CSF strongly induced neutrophils to form NETs in vitro, which was observed in some conditioned media from ovarian cancer cell lines and serum from ovarian cancer patients as well. The adhesion of ovarian cancer cell was increased by co-incubation with NETs. Conclusion: Neutrophilia is associated with peritoneal dissemination and poor prognosis in ovarian cancer. One of the underlying mechanism of neutrophilia is upregulated G-CSF, which stimulate neutrophils to form NETs. NETs may have a causative effect on ovarian cancer dissemination. Citation Format: Gaku Yamamoto, Mahiru Kawano, Michiko Bun, Koutaro Shimura, Aska Toda, Koji Nakamura, Yasuto Kinose, Michiko Kodama, Kae Hashimoto, Kenjiro Sawada, Tadashi Kimura. Ovarian cancer predisposes neutrophils to form neutrophil extracellular traps(NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5329.
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Shelite, Thomas R., Nicole L. Mendell, Donald H. Bouyer, David Hughes Walker y Lynn Soong. "The role of neutrophils during Orientia infection." Journal of Immunology 196, n.º 1_Supplement (1 de mayo de 2016): 66.28. http://dx.doi.org/10.4049/jimmunol.196.supp.66.28.
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Abstract Scrub typhus is a seriously neglected disease with approximately one-third of the world’s population at risk of being infected with Orientia tsutsugamushi, and the occurrence of over one million scrub typhus cases annually illustrate its importance in global health. All scrub typhus case studies that report blood cell counts, describe neutrophilia during the course of infection. Patients with confirmed scrub typhus have significant increases in activated neutrophil proteins in serum, and the increase of neutrophil recruiting cytokines. We also observed neutrophilia as well as neutrophil recruitment to infected tissues in intravenously infected mice, suggesting key role for neutrophils in scrub typhus disease progression. To determine the role of neutrophils in this infection, female C57BL/6 mice were lethally challenged, and neutrophils were depleted one day prior to infection (D−1) or six (D+6) days post infection. The effects of neutrophil depletion were observed to be dependent on the time post infection. Animals depleted early (D-1) exhibited more severe pathology at an earlier time point and had disease progression similar to non-depleted animals but had greater survival. Animals depleted 6 dpi recovered weight, and signs of illness had resolved by 12 dpi. Histopathology demonstrated decreased cellular infiltrates when compared to infected, non-depleted animals. Depletion of neutrophils decreased mortality independent of when depleted, but only depletion 6 dpi resulted in amelioration of signs. These data suggest an important role of neutrophils in tissue pathology and disease progression during scrub typhus infection.
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Hilda, J. Nancy, Sulochana Das, Srikanth P. Tripathy y Luke Elizabeth Hanna. "Role of neutrophils in tuberculosis: A bird's eye view". Innate Immunity 26, n.º 4 (17 de noviembre de 2019): 240–47. http://dx.doi.org/10.1177/1753425919881176.
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Neutrophils are innate immune cells implicated in the process of killing Mycobacterium tuberculosis early during infection. Once the mycobacteria enter the human system, neutrophils sense and engulf them. By secreting bactericidal enzymes and α-defensins like human neutrophil peptides loaded in their granule armory, neutrophils kill the pathogen. Peripheral blood neutrophils secrete a wide range of cytokines like IL-8, IL-1-β and IFN-γ in response to mycobacterial infection. Thus they signal and activate distant immune cells thereby informing them of prevailing infection. The activated monocytes, dendritic cells and T cells further continue the immune response. As a final call, neutrophils release neutrophil extracellular traps in circulation which can trap mycobacteria in patients with active pulmonary tuberculosis. Extensive neutrophilic response is associated with inflammation, pulmonary destruction, and pathology. For example, inappropriate phagocytosis of mycobacteria-infected neutrophils can damage host cells due to necrosis of neutrophils, leading to chronic inflammation and tissue damage. This dual nature of neutrophils makes them double-edged swords during tuberculosis, and hence data available on neutrophil functions against mycobacterium are controversial and non-uniform. This article reviews the role of neutrophils in tuberculosis infection and highlights research gaps that need to be addressed. We focus on our understanding of new research ideologies targeting neutrophils (a) in the early stages of infection for boosting specific immune functions or (b) in the later stages of infection to prevent inflammatory conditions mediated by activated neutrophils. This would plausibly lead to the development of better tuberculosis vaccines and therapeutics in the future.
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Sandri, Silvana, Cristina Bichels Hebeda, Milena Fronza Broering, Marina de Paula Silva, Luciana Facure Moredo, Milton José de Barros e Silva, André Sapata Molina et al. "Role of Annexin A1 Secreted by Neutrophils in Melanoma Metastasis". Cells 12, n.º 3 (27 de enero de 2023): 425. http://dx.doi.org/10.3390/cells12030425.
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Annexin A1 (AnxA1) is highly secreted by neutrophils and binds to formyl peptide receptors (FPRs) to trigger anti-inflammatory effects and efferocytosis. AnxA1 is also expressed in the tumor microenvironment, being mainly attributed to cancer cells. As recruited neutrophils are player cells at the tumor sites, the role of neutrophil-derived AnxA1 in lung melanoma metastasis was investigated here. Melanoma cells and neutrophils expressing AnxA1 were detected in biopsies from primary melanoma patients, which also presented higher levels of serum AnxA1 and augmented neutrophil–lymphocyte ratio (NLR) in the blood. Lung melanoma metastatic mice (C57BL/6; i.v. injected B16F10 cells) showed neutrophilia, elevated AnxA1 serum levels, and higher labeling for AnxA1 in neutrophils than in tumor cells at the lungs with metastasis. Peritoneal neutrophils collected from naïve mice were co-cultured with B16F10 cells or employed to obtain neutrophil-conditioned medium (NCM; 18 h incubation). B16F10 cells co-cultured with neutrophils or with NCM presented higher invasion, which was abolished if B16F10 cells were previously incubated with FPR antagonists or co-cultured with AnxA1 knockout (AnxA1-/-) neutrophils. The depletion of peripheral neutrophils during lung melanoma metastasis development (anti-Gr1; i.p. every 48 h for 21 days) reduced the number of metastases and AnxA1 serum levels in mice. Our findings show that AnxA1 secreted by neutrophils favors melanoma metastasis evolution via FPR pathways, addressing AnxA1 as a potential biomarker for the detection or progression of melanoma.
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Kologrivova, E. N., R. I. Pleshko, O. V. Cheremisina y M. A. Boldyshevskaya. "Hypersegmentation of neutrophil nuclei in peripheral blood of patients with localized and advanced cancer of the larynx and laryngopharynx". Medical Immunology (Russia) 25, n.º 5 (1 de junio de 2023): 1111–16. http://dx.doi.org/10.15789/1563-0625-hon-2715.
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Neutrophilic granulocytes have a wide spectrum of functional activity. In recent years, the functional significance of neutrophils in the development and course of malignant neoplasms has been discussed. It has been shown that neutrophilic granulocytes can play pro- or antitumor activity. The aim of the study was to assess the structural and functional features of neutrophils in patients with varying degrees of prevalence of cancer of the larynx and laryngopharynx. Forty-one patients (aged 35-67) with newly diagnosed cancer of the larynx and laryngopharynx were examined and divided into subgroups according to the TNM classification: the first subgroup (14 patients) with a localized tumor process consisted; and the second subgroup (27 patients) with a widespread tumor process. The relative and absolute number of neutrophils was assessed, and the neutrophil-lymphocyte ratio (NLR) was determined. The content of neutrophils with varying degrees of nuclear segmentation in the blood was calculated, the activity of myeloperoxidase, cationic proteins, alkaline phosphatase, and the degree of neutrophil activation in the NBT test was determined cytochemically. Concentration of interleukin-8 was determined using ELISA. In patients with cancer of the larynx and laryngopharynx the number of neutrophils (p = 0.045) and NLR (p = 0.033), as well as serum concentration of interleukin 8 (p = 0.011), increased compared to healthy individuals. The proportion of cells with hypersegmented nuclei in the neutrophil population (p < 0.001) and cytotoxic potential increased with the spread of tumor process. A direct correlation (r = 0.42, p = 0.03) was found between the T index, which reflects the volume of the tumor, and the content of hypersegmented neutrophils. It can be argued that such a simple and accessible laboratory parameter as the degree of segmentation of the nuclei of neutrophilic granulocytes can be used as one of the criteria to assess and predict the course of the tumor process.
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Bohner, Ariel M., Manasi Gadkari, Michelle Makiya, So Gun Hong, Qilin Cao, E. Lake Potter, Fan Xing et al. "In vivocell tracking reveals the pattern of neutrophil tissue distribution at baseline and in response to glucocorticoid treatment". Journal of Immunology 210, n.º 1_Supplement (1 de mayo de 2023): 79.02. http://dx.doi.org/10.4049/jimmunol.210.supp.79.02.
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Abstract Neutrophils are the most abundant circulating immune cell in humans and primates, and they play a central role in inflammation and innate immunity. Glucocorticoids (GCs) are the cornerstone of anti-inflammatory and immunosuppressive therapies. While GCs are known to induce neutrophilia, little is known about the underlying kinetics or molecular mechanisms. To better define the kinetics of GC-induced neutrophilia, we studied healthy human volunteers and rhesus macaques, and found that the neutrophilia peaks within 4 hours of GC infusion and lasts beyond 72 hours. Flow cytometry, nuclear morphology, and single-cell RNA-seq confirmed that GC-mobilized neutrophils are mature and do not have the CXCR1 lo/ICAM1 hireverse-transmigration phenotype. To study the pattern of neutrophil tissue distribution in vivo, we are performing live tracking of neutrophils by PET/CT and serial intravascular staining (SIVS), before and after GC in a rhesus model. Initial Zr-89 oxine PET/CT results indicate that re-injected radiolabeled neutrophils transit the lungs quickly and within 24 hours localize to the liver, bone marrow, and spleen, where the signal remains stable for at least 72 hours. GC treatment does not appear to lead to significant re-distribution of tissue neutrophils. Initial SIVS results indicate that most GC-mobilized neutrophils had been in circulation for less than a day and came from the intravascular compartment. In summary, our findings to date indicate that neutrophils have stable and prolonged tissue localization, and that GCs rapidly mobilize a small proportion of the total neutrophil pool, composed mainly of mature cells that were present in the intravascular compartment at the time of treatment. supported by grants from NIH (Intramural Research Program – NIAMS/NIH)
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Slavinsky, A. A., L. M. Chuprinenko, V. S. Verevkina y E. S. Sevostyanova. "Blood and cell infiltrate neutrophilic leucocytes As inflammation markers in chronic endometritis: A prospective non-randomised controlled trial". Kuban Scientific Medical Bulletin 28, n.º 2 (15 de abril de 2021): 59–72. http://dx.doi.org/10.25207/1608-6228-2021-28-2-59-72.
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Background. Inflammation declares itself with the presence of cellular tissue infiltrate, which composition reflects the inflammation type. Chronic inflammation is predominated by mononuclear cell infiltration with a certain amount of neutrophils, which role and significance are not fully understood to date.Objectives. Assessment of the infiltrated neutrophil count at various chronic endometritis severity and its dependency on the functional and metabolic activity in neutrophilic leucocytes in peripheral blood.Methods. This prospective non-randomised controlled trial estimated the CD45+ leucocyte and activated CD16b+ neutrophil counts in inflammation infiltrate using immunohistochemistry protocols. Cell counts per section 1 mm2 were measured with computer morphometry. The content of and NADPH oxidase activity in activated neutrophilic leucocytes in venous blood were estimated with a nitroblue tetrazolium reduction test.Results. The study included 40 women with a history of chronic endometritis (CE) divided in two cohorts by endometrial biopsy data, with inactive (n = 25) and active CE (n = 15). A control cohort comprised 20 women with no signs of CE. The inactive CE cohort had higher counts of CD45+ leucocytes and activated CD16b+ neutrophils in infiltrate compared to control. Higher content of activated neutrophilic leucocytes with higher NADPH oxidase activity were found in peripheral blood. Morphological exacerbation markers of EC were associated with sharper peaks of CD45+ and CD16b+ cell counts in infiltrate and an elevated functional metabolic activity in circulating neutrophilic leucocytes. A strong direct correlation was revealed between blood activated neutrophil and endometrial CD16b+ neutrophil counts, as well as NADPH oxidase activity in blood neutrophils and infiltrate CD16b+ cell counts.Conclusion. Even minor morphological markers of exacerbated endometrial inflammation are accompanied by the elevated infiltrate counts of both total CD45+ leucocytes and activated CD16b+ neutrophils. The functional metabolic activity of peripheral blood neutrophilic leucocytes is interlinked with the inflammatory infiltrate cell composition and reflects severity of chronic endometrial inflammation.
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Panova, Veera, Mayuri Gogoi, Noe Rodriguez-Rodriguez, Meera Sivasubramaniam, Helen E. Jolin, Morgan W. D. Heycock, Jennifer A. Walker et al. "Group-2 innate lymphoid cell-dependent regulation of tissue neutrophil migration by alternatively activated macrophage-secreted Ear11". Mucosal Immunology 14, n.º 1 (26 de mayo de 2020): 26–37. http://dx.doi.org/10.1038/s41385-020-0298-2.
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AbstractType-2 immunity is characterised by interleukin (IL)-4, IL-5 and IL-13, eosinophilia, mucus production, IgE, and alternatively activated macrophages (AAM). However, despite the lack of neutrophil chemoattractants such as CXCL1, neutrophils, a feature of type-1 immunity, are observed in type-2 responses. Consequently, alternative mechanisms must exist to ensure that neutrophils can contribute to type-2 immune reactions without escalation of deleterious inflammation. We now demonstrate that type-2 immune-associated neutrophil infiltration is regulated by the mouse RNase A homologue, eosinophil-associated ribonuclease 11 (Ear11), which is secreted by AAM downstream of IL-25-stimulated ILC2. Transgenic overexpression of Ear11 resulted in tissue neutrophilia, whereas Ear11-deficient mice have fewer resting tissue neutrophils, whilst other type-2 immune responses are not impaired. Notably, administration of recombinant mouse Ear11 increases neutrophil motility and recruitment. Thus, Ear11 helps maintain tissue neutrophils at homoeostasis and during type-2 reactions when chemokine-producing classically activated macrophages are infrequently elicited.
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von Vietinghoff, Sibylle, Gisela Tunnemann, Claudia Eulenberg, Maren Wellner, M. Cristina Cardoso, Friedrich C. Luft y Ralph Kettritz. "NB1 mediates surface expression of the ANCA antigen proteinase 3 on human neutrophils". Blood 109, n.º 10 (23 de enero de 2007): 4487–93. http://dx.doi.org/10.1182/blood-2006-10-055327.
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Abstract Antineutrophil cytoplasmic antibodies (ANCAs) with specificity for proteinase 3 (PR3) are central to a form of ANCA-associated vasculitis. Membrane PR3 (mPR3) is expressed only on a subset of neutrophils. The aim of this study was to determine the mechanism of PR3 surface expression on human neutrophils. Neutrophils were isolated from patients and healthy controls, and hematopoietic stem cells from cord blood served as a model of neutrophil differentiation. Surface expression was analyzed by flow cytometry and confocal microscopy, and proteins were analyzed by Western blot experiments. Neutrophil subsets were separated by magnetic cell sorting. Transfection experiments were carried out in HEK293 and HL60 cell lines. Using neutrophils from healthy donors, patients with vasculitis, and neutrophilic differentiated stem cells we found that mPR3 display was restricted to cells expressing neutrophil glycoprotein NB1, a glycosylphosphatidylinositol (GPI)–linked surface receptor. mPR3 expression was decreased by enzymatic removal of GPI anchors from cell membranes and was absent in a patient with paroxysmal nocturnal hemoglobinuria. PR3 and NB1 coimmunoprecipitated from and colocalized on the neutrophil plasma membrane. Transfection with NB1 resulted in specific PR3 surface binding in different cell types. We conclude that PR3 membrane expression on neutrophils is mediated by the NB1 receptor.
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Gordy, Claire, Heather Pua, Gregory D. Sempowski y You-Wen He. "Regulation of steady-state neutrophil homeostasis by macrophages". Blood 117, n.º 2 (13 de enero de 2011): 618–29. http://dx.doi.org/10.1182/blood-2010-01-265959.
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Abstract The timely clearance of apoptotic neutrophils from inflammation sites is an important function of macrophages; however, the role of macrophages in maintaining neutrophil homeostasis under steady-state conditions is less well understood. By conditionally deleting the antiapoptotic gene cellular FLICE-like inhibitory protein (C-FLIP) in myeloid cells, we have generated a novel mouse model deficient in marginal zone and bone marrow stromal macrophages. These mice develop severe neutrophilia, splenomegaly, extramedullary hematopoiesis, decreased body weight, and increased production of granulocyte colony-stimulating factor (G-CSF) and IL-1β, but not IL-17. c-FLIPf/f LysM-Cre mice exhibit delayed clearance of circulating neutrophils, suggesting that failure of macrophages to efficiently clear apoptotic neutrophils causes production of cytokines that drive excess granulopoiesis. Further, blocking G-CSF but not IL-1R signaling in vivo rescues this neutrophilia, suggesting that a G-CSF–dependent, IL-1β–independent pathway plays a role in promoting neutrophil production in mice with defective clearance of apoptotic cells.
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Cain, Derek W., Yoshihiro Ueda, Thomas Matt Holl, Pilar B. Snowden, Motonari Kondo y Garnett Kelsoe. "A comparison of “steady-state” and “emergency” granulopoiesis: evidence of a single pathway for neutrophil production (87.5)". Journal of Immunology 182, n.º 1_Supplement (1 de abril de 2009): 87.5. http://dx.doi.org/10.4049/jimmunol.182.supp.87.5.
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Abstract Normally, neutrophil pools are maintained by steady-state granulopoiesis in bone marrow (BM). Inflammation, however, elicits neutrophilias that outstrip the capacity of steady-state granulopoiesis, and are thought to rely on a distinct program of accelerated production known as "emergency" granulopoiesis. In mice immunized with alum adjuvant, IL-1RI expression by radioresistant cells is required for both the mobilization of neutrophils from BM and increased proliferation by hematopoietic progenitors. Thus, an IL-1RI dependent trans-acting factor(s) mediates the accelerated neutrophil output needed for alum-induced neutrophilias, consistent with models of emergency granulopoiesis where inflammation elicits growth factors, i.e., G-CSF, GM-CSF, IL-3, and IL-6. These models do not, however, explain the emergency-like responses that follow non-inflammatory neutrophil depletion. Similarly, progenitor compartments are constitutively expanded in mice rendered neutropenic by the conditional loss of Mcl-1. Our observations suggest that neutrophilias elicited by inflammation are not the result of a distinct pathway of granulopoiesis, but represent the stabilizing effects of feedback that correct for the loss of BM neutrophils. We propose that inflammatory signals decrease the number of BM neutrophils via mobilization to increase progenitor proliferation through a homeostatic mechanism. Research support: NIH grants AI24335 and AI56363 (to G.K.)
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Teddleton, Hannah G., Scott P. Greiner y Scott A. Bowdridge. "21 Ancylostoma caninum-derived neutrophil inhibitory factor impairs ovine neutrophil chemotaxis to Haemonchus contortus larval antigen in Suffolk but not St. Croix sheep". Journal of Animal Science 102, Supplement_1 (1 de marzo de 2024): 56–57. http://dx.doi.org/10.1093/jas/skae019.067.
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Abstract Parasite-resistant St. Croix sheep (STC) generate a potent neutrophilic response to larval stages of Haemonchus contortus (Hc) as demonstrated by abomasal neutrophil infiltration as early as 3 days after infection. This phenomenon is delayed in parasite-susceptible Suffolk sheep (SUF) potentially contributing to larval establishment. An excretory/secretory (E/S) product, common to many helminths, is neutrophil inhibitory factor (NIF) which negatively affects neutrophil migration and activity. Due to differences in neutrophil accumulation between STC and SUF sheep, we hypothesized that Hc-NIF may inhibit migration of SUF and not STC neutrophils. To determine the concentration of NIF to use in subsequent experiments, neutrophils from STC and SUF were cultured with varying concentrations of Ancylostoma caninum-derived NIF (Ac-NIF) before exposure to larval Hc third-stage larval antigen (HcLA). Analysis of migration to stimuli revealed that the Ac-NIF concentration of 0.125 ug/mL yielded the greatest inhibition of migration towards HcLA between SUF and STC (8.70% and 11.64% migration, respectively; P = 0.0004).To test our hypothesis, neutrophils were cultured from STC and SUF sheep in the presence of Ancylostoma caninum-derived NIF (Ac-NIF) and measure chemotaxis to Interleukin-8 (IL-8), HcLA or Hc third-stage excretory/secretory (E/S) products. Neutrophils were isolated then incubated with Ac-NIF (0.125μg/mL) or complete media for 1 h. Neutrophils (1,000,000 cell/mL) were applied to cell migration inserts, and placed into a reservoir containing HcLA (20 μg/mL), E/S (20 μg/mL), IL-8 (50 ng/mL), or complete media. Migration plates were incubated (37°C, 5% CO2) for 24 h, after which, migrating cells were quantified using fluorescence. Ac-NIF inhibited SUF neutrophil migration towards IL-8 compared with STC (6.47% vs 9.95%, respectively; P = 0.0025). In response to HcLA alone, 64.0% of STC neutrophils migrated, while only 40.9% of SUF had the ability to migrate (P < 0.001). Towards HcLA, Ac-NIF inhibited SUF neutrophil migration compared with STC (8.40% vs 13.8%, respectively) (P < 0.001). Even more dramatically, in response to E/S products alone, only 24.3% of SUF neutrophils had the ability to migrate, while 76.4% of STC neutrophils migrated towards E/S (P < 0.001). In response to E/S, only 1.52% of SUF Ac-NIF-treated neutrophils were able to migrate, while 23.27% of STC neutrophils migrated (P < 0.001). Taken together, these data demonstrate that STC neutrophils are resistant to effects of neutrophil inhibition that is artificially applied or derived from HcE/S, which may explain breed differences in neutrophil migration in vivo.
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Lodge, Katharine M., Andrew S. Cowburn, Wei Li y Alison M. Condliffe. "The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host". International Journal of Molecular Sciences 21, n.º 4 (11 de febrero de 2020): 1183. http://dx.doi.org/10.3390/ijms21041183.
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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.
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Terashi, Kenji, Mikio Oka, Shigehiro Ohdo, Taku Furukubo, Chizuko Ikeda, Minoru Fukuda, Hiroshi Soda, Shun Higuchi y Shigeru Kohno. "Close Association between Clearance of Recombinant Human Granulocyte Colony-Stimulating Factor (G-CSF) and G-CSF Receptor on Neutrophils in Cancer Patients". Antimicrobial Agents and Chemotherapy 43, n.º 1 (1 de enero de 1999): 21–24. http://dx.doi.org/10.1128/aac.43.1.21.
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ABSTRACT Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is used to counter chemotherapy-induced neutropenia. Our previous study showed an inverse correlation between serum rhG-CSF levels and the number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and M. Oka, Antimicrob. Agents Chemother. 40:988–991, 1996). The aim of this study was to clarify the relationship between rhG-CSF clearance and G-CSF receptors on circulating neutrophils. In five cancer patients receiving chemotherapy, a bolus dose of rhG-CSF (5 μg/kg) was injected intravenously during defined phases of posttreatment neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a chemiluminescence enzyme immunoassay and analyzed by moment analysis. G-CSF receptors on neutrophils were detected by flow cytometry with biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at neutrophilia than at neutropenia (1,497 ± 132 versus 995 ± 266 ml/h; P < 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors per cell, was low at neutropenia without rhG-CSF therapy (44.5% ± 22.1%) and high at neutrophilia with rhG-CSF therapy (73.0% ± 11.4%; P < 0.01). rhG-CSF clearance closely correlated with the percentage of G-CSF receptor-positive neutrophils (r 2 = 0.91; P < 0.0001) and neutrophil count (r 2 = 0.72; P < 0.005). Our results indicate that, in cancer patients receiving chemotherapy, rhG-CSF increases the number of G-CSF receptors per cell as well as circulating neutrophil counts, resulting in modulation of its own clearance.
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Hsu, Alan Y., Decheng Wang, Sheng Liu, Justice Lu, Ramizah Syahirah, David A. Bennin, Anna Huttenlocher, David M. Umulis, Jun Wan y Qing Deng. "Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration". Proceedings of the National Academy of Sciences 116, n.º 37 (26 de agosto de 2019): 18561–70. http://dx.doi.org/10.1073/pnas.1905221116.
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Neutrophil migration is essential for inflammatory responses to kill pathogens; however, excessive neutrophilic inflammation also leads to tissue injury and adverse effects. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA (miRNA) overexpression screen in zebrafish and identified 8 miRNAs as potent suppressors of neutrophil migration. Among those,miR-199decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils,miR-199alters the cell cycle-related pathways and directly suppresses cyclin-dependent kinase 2 (Cdk2), whose known activity is restricted to cell cycle progression and cell differentiation. Inhibiting Cdk2, but not DNA replication, disrupts cell polarity and chemotaxis of zebrafish neutrophils without inducing cell death. Human neutrophil-like cells deficient in CDK2 fail to polarize and display altered signaling downstream of the formyl peptide receptor. Chemotaxis of primary human neutrophils is also reduced upon CDK2 inhibition. Furthermore,miR-199overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Our results therefore reveal previously unknown functions ofmiR-199and CDK2 in regulating neutrophil migration and provide directions in alleviating systemic inflammation.
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Song, Zhimin, Guangming Huang, Luana Chiquetto Paracatu, Derayvia Grimes, Jiwei Gu, Cliff J. Luke, Regina A. Clemens y Mary C. Dinauer. "NADPH oxidase controls pulmonary neutrophil infiltration in the response to fungal cell walls by limiting LTB4". Blood 135, n.º 12 (19 de marzo de 2020): 891–903. http://dx.doi.org/10.1182/blood.2019003525.
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Abstract Leukocyte reduced NADP (NADPH) oxidase plays a key role in host defense and immune regulation. Genetic defects in NADPH oxidase result in chronic granulomatous disease (CGD), characterized by recurrent bacterial and fungal infections and aberrant inflammation. Key drivers of hyperinflammation induced by fungal cell walls in CGD are still incompletely defined. In this study, we found that CGD (CYBB−) neutrophils produced higher amounts of leukotriene B4 (LTB4) in vitro after activation with zymosan or immune complexes, compared with wild-type (WT) neutrophils. This finding correlated with increased calcium influx in CGD neutrophils, which was restrained in WT neutrophils by the electrogenic activity of NADPH oxidase. Increased LTB4 generation by CGD neutrophils was also augmented by paracrine cross talk with the LTB4 receptor BLT1. CGD neutrophils formed more numerous and larger clusters in the presence of zymosan in vitro compared with WT cells, and the effect was also LTB4- and BLT1-dependent. In zymosan-induced lung inflammation, focal neutrophil infiltrates were increased in CGD compared with WT mice and associated with higher LTB4 levels. Inhibiting LTB4 synthesis or antagonizing the BLT1 receptor after zymosan challenge reduced lung neutrophil recruitment in CGD to WT levels. Thus, LTB4 was the major driver of excessive neutrophilic lung inflammation in CGD mice in the early response to fungal cell walls, likely by a dysregulated feed-forward loop involving amplified neutrophil production of LTB4. This study identifies neutrophil LTB4 generation as a target of NADPH oxidase regulation, which could potentially be exploited therapeutically to reduce excessive inflammation in CGD.
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Kumar, Sachin, Juying Xu, Magdalena Chrzanowska-Wodnicka y Marie-Dominique Filippi. "The Small Gtpase Rap1b Negatively Regulates Neutrophil Migration During Inflammation By Limiting Trans-Cellular Diapedesis". Blood 122, n.º 21 (15 de noviembre de 2013): 320. http://dx.doi.org/10.1182/blood.v122.21.320.320.
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Abstract Neutrophils are the first line of cellular defense against infecting microorganisms by moving rapidly toward sites of infection. Impaired neutrophil recruitment and functions can cause life-threatening infections, while excessive neutrophil tissue infiltration contributes to inflammatory disorders and tissue injury. A number of key positive regulators of neutrophil tissue infiltration have been identified. However, the mechanisms that protect from unwanted inflammation by negative regulation of neutrophil recruitment and functions are still unrecognized. Rap1b is an evolutionary conserved protein of the Ras-like GTPase superfamily. The mammalian genome encodes two Rap1 genes, Rap1a and Rap1b, which are highly homologous. Rap1 is historically known to control functional activation of integrins to positively regulate a number of cellular processes, including cell adhesion, cell polarity, cell migration, platelet aggregation. Rap1b is the main Rap1 isoform expressed in neutrophils; yet, its functions in neutrophils are poorly understood. Here, we found that, quite unexpectedly, Rap1b is a key suppressor of neutrophil migration, and inflammation. Rap1b loss enhanced neutrophil emigration into lungs, associated with increased susceptibility to endotoxin shock. To further understand the role of Rap1b in neutrophil migration, we used a 3-D migration assay in which neutrophils are plated onto activated endothelial cells. This assay enables examination of critical steps of the extravasation cascade, ie neutrophil adhesion onto the endothelium, lateral crawling to the nearest endothelial cell junction and permissive sites for transmigration. This assay confirmed increased transendothelial migration of Rap1b-/- neutrophils compared to WT cells. However, Rap1b-/- neutrophils were unable to reach endothelial junction and shifted their mode of transmigration to a trans-cellular (through endothelial cells) diapedesis instead of the canonical paracellular route (between two endothelial cells). Indeed, using immunostaining with VE-Cadherin, ICAM-1 and CD11b to identify endothelial junctions and neutrophils, respectively, we found only 5-10% WT neutrophils used the transcellular route of diapedesis. Up to 30-35% Rap1b–/– neutrophils transmigrated via the transcellular route. Transcellular diapedesis requires the formation of invadopodia-like actin protrusions, an extracellular matrix-degrading structure enabling penetration into tissue. Transmission electron microscopy indicated increased invadopodia-like structures in Rap1b–/– neutrophils that penetrated deeper into endothelial surfaces than WT cells. Likewise, Rap1b–/– neutrophils had increased ability to degrade gelatin matrix in vitro. Mechanistically, the Rap1b-null phenotype was mediated by enhanced Pi3K-Akt activation. Rap1b-/- neutrophils manifested increased phosphorylation of Akt, in response to chemokine and integrin stimuli. Treatment of a small molecule Akt inhibitor, MK-2206 reversed elevated transmigration, matrix degradation and rescued crawling of Rap1b–/– neutrophils to endothelial junctions. Importantly, Akt inhibition in vivo suppressed excessive Rap1b–/– neutrophil migration into lungs and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by the phosphatase SHP-1, as its activation and localization was Rap1b-dependent. These findings uncover a novel mechanism of neutrophil migration, and reveal an unexpected role for Rap1b as a key suppressor of neutrophilic lung inflammation. This work has far reaching importance for inflammatory processes. It may represent new avenues for the treatment of pathological inflammation conditions. Disclosures: No relevant conflicts of interest to declare.
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Kast, Richard E. "Research Supporting a Pilot Study of Metronomic Dapsone during Glioblastoma Chemoirradiation". Medical Sciences 9, n.º 1 (16 de febrero de 2021): 12. http://dx.doi.org/10.3390/medsci9010012.
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This short note presents previous research data supporting a pilot study of metronomic dapsone during the entire course of glioblastoma treatment. The reviewed data indicate that neutrophils are an integral part of human glioblastoma pathophysiology, contributing to or facilitating glioblastoma growth and treatment resistance. Neutrophils collect within glioblastoma by chemotaxis along several chemokine/cytokine gradients, prominently among which is interleukin-8. Old data from dermatology research has shown that the old and inexpensive generic drug dapsone inhibits neutrophils’ chemotaxis along interleukin-8 gradients. It is on that basis that dapsone is used to treat neutrophilic dermatoses, for example, dermatitis herpetiformis, bullous pemphigoid, erlotinib-related rash, and others. The hypothesis of this paper is that dapsone will reduce glioblastomas’ neutrophil accumulations by the same mechanisms by which it reduces dermal neutrophil accumulations in the neutrophilic dermatoses. Dapsone would thereby reduce neutrophils’ contributions to glioblastoma growth. Dapsone is not an ideal drug, however. It generates methemoglobinemia that occasionally is symptomatic. This generation is reduced by concomitant use of the antacid drug cimetidine. Given the uniform lethality of glioblastoma as of 2020, the risks of dapsone 100 mg twice daily and cimetidine 400 mg twice daily is low enough to warrant a judicious pilot study.
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Lira, S. A., P. Zalamea, J. N. Heinrich, M. E. Fuentes, D. Carrasco, A. C. Lewin, D. S. Barton, S. Durham y R. Bravo. "Expression of the chemokine N51/KC in the thymus and epidermis of transgenic mice results in marked infiltration of a single class of inflammatory cells." Journal of Experimental Medicine 180, n.º 6 (1 de diciembre de 1994): 2039–48. http://dx.doi.org/10.1084/jem.180.6.2039.
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Transgenic mice expressing the chemokine N51/KC in thymus, skin, and tongue showed a marked infiltration of a single class of inflammatory cells (neutrophils) in the sites of transgene expression. In the thymus, neutrophils were most numerous in the cortex and juxta-medullary regions, often forming aggregates or clusters. A similar, but less intense, neutrophilic infiltrate occurred in close proximity to the epidermal basal layer of the tongue and skin. No morphologic evidence of injury was observed in the thymus, skin, or tongue of these transgenic mice, indicating that N51/KC expression induces recruitment but not inflammatory activation of neutrophils. The lack of activation in the thymus resulted in a large senescent neutrophilic population that was phagocytosed by thymic macrophages and epithelial-reticular cells. These results indicate that N51/KC is a neutrophil chemoattractant in vivo and establish these transgenic mice as effective models to study the phenomena of recruitment and clearance of neutrophils, events that are critical for the initiation and resolution of the inflammatory response.
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Zheng, Leyu, Moujie Rang, Carolin Fuchs, Annette Keß, Mandy Wunsch, Julia Hentschel, Cheng-Chih Hsiao, Christian Kleber, Georg Osterhoff y Gabriela Aust. "The Posttraumatic Increase in the Adhesion of GPCR EMR2/ADGRE2 to Circulating Neutrophils Is Not Related to Injury Severity". Cells 12, n.º 22 (20 de noviembre de 2023): 2657. http://dx.doi.org/10.3390/cells12222657.
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Trauma triggers a rapid innate immune response to aid the clearance of damaged/necrotic cells and their released damage-associated molecular pattern (DAMP). Here, we monitored the expression of EMR2/ADGRE2, involved in the functional regulation of innate immune cells, on circulating neutrophils in very severely and moderately/severely injured patients up to 240 h after trauma. Notably, neutrophilic EMR2 showed a uniform, injury severity- and type of injury-independent posttraumatic course in all patients. The percentage of EMR2+ neutrophils and their EMR2 level increased and peaked 48 h after trauma. Afterwards, they declined and normalized in some, but not all, patients. Circulating EMR2+ compared to EMR2− neutrophils express less CD62L and more CD11c, a sign of activation. Neutrophilic EMR2 regulation was verified in vitro. Remarkably, it increased, depending on extracellular calcium, in controls as well. Cytokines, enhanced in patients immediately after trauma, and sera of patients did not further affect this neutrophilic EMR2 increase, whereas apoptosis induction disrupted it. Likely the damaged/necrotic cells/DAMPs, unavoidable during neutrophil culture, stimulate the neutrophilic EMR2 increase. In summary, the rapidly increased absolute number of neutrophils, especially present in very severely injured patients, together with upregulated neutrophilic EMR2, may expand our in vivo capacity to react to and finally clear damaged/necrotic cells/DAMPs after trauma.
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Badve, Sunil, Andrea Blumstein, Peter Wiernik y Howard Ratech. "Non-Hodgkin Malignant Lymphoma With Tissue Neutrophilia". Archives of Pathology & Laboratory Medicine 124, n.º 5 (1 de mayo de 2000): 735–38. http://dx.doi.org/10.5858/2000-124-0735-nhmlwt.
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Abstract Context.—Neutrophils, in the absence of necrosis, are uncommon in non-Hodgkin malignant lymphoma. Recently, a neutrophil-rich type of Ki-1 (CD30)-positive, anaplastic large cell lymphoma was described. Objectives.—We report 3 cases of nonanaplastic large cell lymphoma with an abundance of tissue neutrophils; 2 cases were associated with breast carcinoma and possible infection. Results.—Peripheral blood neutrophilia was noted in only 1 of these 3 patients. Neutrophilia in the lymph nodes occurred in either a sinusoidal or interstitial pattern. Multiple biopsies were available for review in 2 patients; however, tissue neutrophilia was present in only 1 biopsy each. Conclusion.—These findings suggest that nonanaplastic large cell lymphoma–related tissue neutrophilia is a transient phenomenon.
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Sládek, Z. y D. Ryšánek. "Apoptosis of neutrophilic granulocytes of bovine virgin mammary gland in scanning electron microscopy". Veterinární Medicína 46, No. 7–8 (1 de enero de 2001): 185–89. http://dx.doi.org/10.17221/7881-vetmed.
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The objective of this work was the morphologic analysis of apoptosis of neutrophilic granulocytes (hereinafter referred to as neutrophils) in scanning electron microscopy (SEM) in comparison with morphological features distinguishable by light microscopy. This study was performed on 12 bovine virgin mammary glands washed with physiological buffered solution (PBS) prior to the induction of cell influx by PBS. Twenty-four hours after influx induction the cell suspension was obtained by the lavage of mammary glands with PBS. The particular lavages were cytologicaly and bacteriologicaly examined. all bacteriological examinations were negative. Mononuclear phagocytes (MoP), lymphocytes and neutrophils were distinguished in the cell suspension of the lavages by means of light microscopy. The neutrophils predominated in differential cell count. Neutrophil population showed some signs of structural features typical for the process of apoptosis that were distinguished in haemocytometer and light microscopy on stained microscopical smears. The process of apoptosis consisted of three structurally different stages: karyopyknosis, zeiosis and the stage of apoptotic bodies. These stages of neutrophil apoptosis were distinguished also by SEM. Karyopyknotic neutrophils assumed spherical shape while they lost all of their superficial pseudopodia. Neutrophils in zeiosis stage showed prominent surface protumberances, bubble-shaped vesicles causing a bizarre deformation of the cells. After the membrane vesicles had split off, they began to form spherical formations (apoptotic bodies). On the basis of neutrophils. specific structural properties it could easily distinguish all the three stages of neutrophil apoptosis by means of SEM technique as well as other morphological methods.
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Jasper, Alice E., William J. McIver, Elizabeth Sapey y Georgia M. Walton. "Understanding the role of neutrophils in chronic inflammatory airway disease". F1000Research 8 (26 de abril de 2019): 557. http://dx.doi.org/10.12688/f1000research.18411.1.
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Airway neutrophilia is a common feature of many chronic inflammatory lung diseases and is associated with disease progression, often regardless of the initiating cause. Neutrophils and their products are thought to be key mediators of the inflammatory changes in the airways of patients with chronic obstructive pulmonary disease (COPD) and have been shown to cause many of the pathological features associated with disease, including emphysema and mucus hypersecretion. Patients with COPD also have high rates of bacterial colonisation and recurrent infective exacerbations, suggesting that neutrophil host defence mechanisms are impaired, a concept supported by studies showing alterations to neutrophil migration, degranulation and reactive oxygen species production in cells isolated from patients with COPD. Although the role of neutrophils is best described in COPD, many of the pathological features of this disease are not unique to COPD and also feature in other chronic inflammatory airway diseases, including asthma, cystic fibrosis, alpha-1 anti-trypsin deficiency, and bronchiectasis. There is increasing evidence for immune cell dysfunction contributing to inflammation in many of these diseases, focusing interest on the neutrophil as a key driver of pulmonary inflammation and a potential therapeutic target than spans diseases. This review discusses the evidence for neutrophilic involvement in COPD and also considers their roles in alpha-1 anti-trypsin deficiency, bronchiectasis, asthma, and cystic fibrosis. We provide an in-depth assessment of the role of the neutrophil in each of these conditions, exploring recent advances in understanding, and finally discussing the possibility of common mechanisms across diseases.
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Mittmann, Laura A., Florian Haring, Johanna B. Schaubächer, Roman Hennel, Bojan Smiljanov, Gabriele Zuchtriegel, Martin Canis et al. "Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression". Journal for ImmunoTherapy of Cancer 9, n.º 12 (diciembre de 2021): e003495. http://dx.doi.org/10.1136/jitc-2021-003495.
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BackgroundBeyond their fundamental role in homeostasis and host defense, neutrophilic granulocytes (neutrophils) are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, aging of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their homeostatic and anti-infectious functional properties. The role of neutrophil aging in cancer remains largely obscure.MethodsEmploying advanced in vivo microscopy techniques in different animal models of cancer as well as utilizing pulse-labeling and cell transfer approaches, various ex vivo/in vitro assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer.ResultsHere, we show that signals released during early tumor growth accelerate biological aging of circulating neutrophils, hence uncoupling biological from chronological aging of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with potent protumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological aging of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.ConclusionsOur data uncover a self-sustaining mechanism of malignant neoplasms in fostering protumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might therefore provide a novel, already pharmacologically targetable strategy for cancer immunotherapy.
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Kolli, Deepthi, Zhang Yueqing, Kimberly Palkowetz, Roberto Garofalo y Antonella Casola. "Critical role of Neutrophils in Respiratory Syncytial Virus (RSV) induced disease pathogenesis (INC8P.440)". Journal of Immunology 192, n.º 1_Supplement (1 de mayo de 2014): 187.13. http://dx.doi.org/10.4049/jimmunol.192.supp.187.13.
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Abstract Neutrophils comprise the largest number of immune cells in the human body, and being the first immune cells to the site of injury and infection, neutrophils act as the first line of defense against harmful pathogens. RSV has been identified as a leading cause of respiratory tract illness in children worldwide. RSV induced disease is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia. The role of neutrophils in innate immune responses to RSV infection has not been fully characterized. We have employed anti-Ly6G clone monoclonal antibody 1A8 to specifically deplete neutrophils in Balb/c mice to study the role of neutrophils in RSV induced disease pathogenesis. Neutrophil depletion in mice infected with RSV A2 or Long strain caused a significant increase in body weight loss, airway hyper responsiveness and lung inflammation. Even though no effect on peak viral replication was observed; a significant reduction in early viral load and a delayed viral clearance in mice lacking neutrophils were observed. While depletion of neutrophils has no effect on the production of BAL type I IFNs, a significant increase in Th17 group of cytokines (IL-17A, IL-17F, IL-22, IL-23p19 and CD40L), G-CSF, KC and MIP-1β was observed. Moreover, we observed a significant reduction in lung DCs, pDCs and virus specific CD4 and CD8 cells in neutrophil depleted mice. Our study demonstrates that neutrophils play a critical role in disease progression of RSV infections.
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Fiedler, Katja, Anca Sindrilaru, Grzegorz Terszowski, Enikö Kokai, Thorsten B. Feyerabend, Lars Bullinger, Hans-Reimer Rodewald y Cornelia Brunner. "Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X-linked agammaglobulinemia". Blood 117, n.º 4 (27 de enero de 2011): 1329–39. http://dx.doi.org/10.1182/blood-2010-04-281170.
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Abstract Bruton tyrosine kinase (Btk) is essential for B cell development and function and also appears to be important for myeloid cells. The bone marrow of Btk-deficient mice shows enhanced granulopoiesis compared with that of wild-type mice. In purified granulocyte-monocyte-progenitors (GMP) from Btk-deficient mice, the development of granulocytes is favored at the expense of monocytes. However, Btk-deficient neutrophils are impaired in maturation and function. Using bone marrow chimeras, we show that this defect is cell-intrinsic to neutrophils. In GMP and neutrophils, Btk plays a role in GM-CSF– and Toll-like receptor–induced differentiation. Molecular analyses revealed that expression of the lineage-determining transcription factors C/EBPα, C/EBPβ, and PU.1, depends on Btk. In addition, expression of several granule proteins, including myeloperoxidase, neutrophilic granule protein, gelatinase and neutrophil elastase, is Btk-dependent. In the Arthus reaction, an acute inflammatory response, neutrophil migration into tissues, edema formation, and hemorrhage are significantly reduced in Btk-deficient animals. Together, our findings implicate Btk as an important regulator of neutrophilic granulocyte maturation and function in vivo.