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Effects of recombinant human lactoferrin on calcium signaling and functional responses of human neutrophils.
Grigorieva, DV, Gorudko, IV, Shamova, EV, Terekhova, MS, Maliushkova, EV, Semak, IV, Cherenkevich, SN, Sokolov, AV, Timoshenko, AV
Archives of biochemistry and biophysics. 2019;:108122
Abstract
Lactoferrin is a non-heme iron-binding glycoprotein with multiple health-beneficial functions including antimicrobial, antioxidant, anticarcinogenic, and immunomodulatory effects. There is emerging evidence that neutrophils may serve as targets of lactoferrin in vivo, and here we show how recombinant human lactoferrin (rhLf) can contribute to this regulation. Indeed, our results demonstrate that rhLf binds efficiently to human neutrophils and induces a variety of early cellular responses such as mobilization of intracellular Ca2+, remodeling of actin cytoskeleton, and degranulation (release of lysozyme and myeloperoxidase). In addition, rhLf facilitates lectin-induced H2O2 production and stabilization of lectin-induced cellular aggregates. The role of calcium signaling seems to be essential for rhLf-induced activation of neutrophils, as Ca2+-chelators inhibit degranulation response while lectin-induced H2O2 production correlates significantly with cytoplasmic Ca2+ elevation. Taken together, our findings justify that rhLf can activate neutrophil functions in a calcium-dependent manner and hence, can potentiate innate immune responses.
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Incorporation of dynamic segmented neutrophil-to-monocyte ratio with leukocyte count for sepsis risk stratification.
Fang, WF, Chen, YM, Wang, YH, Huang, CH, Hung, KY, Fang, YT, Chang, YC, Lin, CY, Chang, YT, Chen, HC, et al
Scientific reports. 2019;(1):19756
Abstract
The association between sepsis and segmented neutrophil-to-monocyte (SeMo) ratio is unclear. We postulated that an increase in dynamic SeMo ratio measurement can be applied in risk stratification. This retrospective study included 727 consecutive sepsis patients in medical intensive care units (ICUs), including a subpopulation of 153 patients. According to the leukocyte (white blood cell, WBC) count on day 3 (normal range, between 4,000/µL and 12,000/µL) and delta SeMo (value of SeMo ratio on day 3 minus value of SeMo ratio on day 1; normal delta SeMo, <7), patients were grouped into 3 (delta SeMo & WBC tool). The survival lines separated significantly with hazard ratios of 1.854 (1.342-2.560) for the delta SeMo or WBC abnormal group and 2.860 (1.849-4.439) for the delta SeMo and WBC abnormal group compared to the delta SeMo and WBC normal group. Delta SeMo & WBC tool and delta sequential organ failure assessment (SOFA) tool performed better than the other tools (delta SeMo, delta WBC, day 3 WBC, and day 1 WBC). Severity in delta SeMo & WBC tool and delta SeMo tool reflected the immune dysfunction score, cytokine expression, and human leukocyte antigen D-related monocyte expression on day 1 and day 3. There was correspondence between delta SOFA and delta WBC and between delta SeMo and delta cytokine expression. Incorporation of dynamic SeMo ratio with WBC count provides risk stratification for sepsis patients admitted in the ICU.
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Neutrophil extracellular traps (NET) induced by different stimuli: A comparative proteomic analysis.
Petretto, A, Bruschi, M, Pratesi, F, Croia, C, Candiano, G, Ghiggeri, G, Migliorini, P
PloS one. 2019;(7):e0218946
Abstract
Neutrophil extracellular traps (NET) formation is part of the neutrophil response to infections, but excessive or inappropriate NETosis may trigger the production of autoantibodies and cause organ damage in autoimmune disorders. Spontaneously netting neutrophils are not frequent and induction of NET in vitro by selected stimuli is necessary to investigate their structure. In the present work, the protein composition and post-translational modifications of NET produced under different stimuli have been studied by means of proteomic analysis. Neutrophils from healthy donors were stimulated by PMA, A23187, Escherichia coli LPS or untreated; after three hours, cells were washed, treated with DNase and supernatants collected for mass spectrometry. Data were analyzed by unsupervised hierarchical clustering analyses. We identified proteins contained in NETs of any source or exclusive of one stimulus: LPS-induced and spontaneous NET diverge in protein composition, while PMA- and A23187-induced NET appear more similar. Among the post-translational modifications we examined, methionine sulfoxidation is frequent especially in PMA- and LPS-induced NETs. Myeloperoxidase is the protein more extensively modified. Thus, proteomic analysis indicates that NETs induced by different stimuli are heterogeneous in terms of both protein composition and post-translational modifications, suggesting that NET induced in different conditions may have different biological effects.
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4.
Complement factor H family proteins in their non-canonical role as modulators of cellular functions.
Józsi, M, Schneider, AE, Kárpáti, É, Sándor, N
Seminars in cell & developmental biology. 2019;:122-131
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Abstract
Complement factor H is a major regulator of the alternative pathway of the complement system. The factor H-related proteins are less characterized, but recent data indicate that they rather promote complement activation. These proteins have some common ligands with factor H and have both overlapping and distinct functions depending on domain composition and the degree of conservation of amino acid sequence. Factor H and some of the factor H-related proteins also appear in a non-canonical function that is beyond their role in the modulation of complement activation. This review covers our current understanding on this emerging role of factor H family proteins in modulating the activation and function of various cells by binding to receptors or receptor ligands.
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Gamma tocopherol effect on LPS-induced sputum neutrophilia is not modified by BMI or GSTM1 genotype.
Sood, AK, Burbank, AJ, Duran, CG, Enders, K, Zhou, H, Peden, DB, Hernandez, ML
The Journal of allergy and clinical immunology. 2019;(5):1937-1939
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Abstract
Gamma tocopherol may be beneficial as a primary or complementary therapeutic agent in conditions with neutrophilic airway inflammation. Its effects are not modified by BMI or GSTM1 genotype, allowing for its use in a broader population.
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Does Neutrophil Phenotype Predict the Survival of Trauma Patients?
Mortaz, E, Zadian, SS, Shahir, M, Folkerts, G, Garssen, J, Mumby, S, Adcock, IM
Frontiers in immunology. 2019;:2122
Abstract
According to the World Health Organization (WHO), trauma is responsible for 10% of deaths and 16% of disabilities worldwide. This is considerably higher than those for malaria, tuberculosis, and HIV/AIDS combined. While the human suffering and death caused by injury is well-recognized, injury has a significant medical care cost. Better prediction of the state of trauma patients in the days immediately after trauma may reduce costs. Traumatic injuries to multiple organs can cause dysfunction in all systems of the body especially the immune system placing patients at high risk of infections and inflammatory complications which are often fatal. Neutrophils are the most abundant leukocyte in the human circulation and are crucial for the prevention of microbial disease. Significant changes in neutrophil functions such as enhanced chemotaxis, Neutrophil extracellular trap (NET)-induced cell death (NETosis), and phagocytosis occur early after injury followed by prolonged functional defects such as phagocytosis, killing mechanisms, and receptor expression. Analysis of these changes may improve the prediction of the patient's condition over time. We provide a comprehensive and up-to-date review of the literature investigating the effect of trauma on neutrophil phenotype with an underlying goal of using this knowledge to examine the predictive potential of neutrophil alterations on secondary complications in patients with traumatic injuries. We conclude that alterations in neutrophil surface markers and functions may be potential biomarkers that predict the outcome of trauma patients.
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Staphylococcus aureus versus neutrophil: Scrutiny of ancient combat.
Nasser, A, Moradi, M, Jazireian, P, Safari, H, Alizadeh-Sani, M, Pourmand, MR, Azimi, T
Microbial pathogenesis. 2019;:259-269
Abstract
Staphylococcus aureus (S.aureus) is a Gram-positive bacterium that causes many infections and diseases. This pathogen can cause many types of infections such as impetigo, toxic shock syndrome toxin (TSST1), pneumonia, endocarditis, and autoimmune diseases like lupus erythematosus and can infect other healthy individuals. In the pathogenic process, colonization is a main risk factor for invasive diseases. Various factors including the cell wall-associated factors and receptors of the epithelial cells facilitate adhesion and colonization of this pathogen. S. aureus has many enzymes, toxins, and strategies to evade from the immune system either by an enzyme that lyses cellular component or by hiding from the immune system via surface antigens like protein A and second immunoglobulin-binding protein (Sbi). The strategies of this bacterium can be divided into five groups: A: Inhibit neutrophil recruitment B: Inhibit phagocytosis C: Inhibit killing by ROS, D: Neutrophil killing, and E: Resistance to antimicrobial peptide. On the other hand, innate immune system via neutrophils, the most important polymorphonuclear leukocytes, fights against bacterial cells by neutrophil extracellular trap (NET). In this review, we try to explain the role of each factor in immune evasion.
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Strategies to generate functionally normal neutrophils to reduce infection and infection-related mortality in cancer chemotherapy.
Abdel-Azim, H, Sun, W, Wu, L
Pharmacology & therapeutics. 2019;:107403
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Abstract
Neutrophils form an essential part of innate immunity against infection. Cancer chemotherapy-induced neutropenia (CCIN) is a condition in which the number of neutrophils in a patient's bloodstream is decreased, leading to increased susceptibility to infection. Granulocyte colony-stimulating factor (GCSF) has been the only approved treatment for CCIN over two decades. To date, CCIN-related infection and mortality remain a significant concern, as neutrophils generated in response to administered GCSF are functionally immature and cannot effectively fight infection. This review summarizes the molecular regulatory mechanisms of neutrophil granulocytic differentiation and innate immunity development, dissects the biology of GCSF in myeloid expansion, highlights the shortcomings of GCSF in CCIN treatment, updates the recent advance of a selective retinoid agonist that promotes neutrophil granulocytic differentiation, and evaluates the benefits of developing GCSF biosimilars to increase access to GCSF biologics versus seeking a new mode to fundamentally advance GCSF therapy for treatment of CCIN.
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Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial.
Ebrahimi, F, Giaglis, S, Hahn, S, Blum, CA, Baumgartner, C, Kutz, A, van Breda, SV, Mueller, B, Schuetz, P, Christ-Crain, M, et al
The European respiratory journal. 2018;(4)
Abstract
Neutrophil extracellular traps (NETs) are a hallmark of the immune response in inflammatory diseases. However, the role of NETs in community-acquired pneumonia (CAP) is unknown. This study aims to characterise the impact of NETs on clinical outcomes in pneumonia.This is a secondary analysis of a randomised controlled, multicentre trial. Patients with CAP were randomly assigned to either 50 mg prednisone or placebo for 7 days. The primary end-point was time to clinical stability; main secondary end-points were length of hospital stay and mortality.In total, 310 patients were included in the analysis. Levels of cell-free nucleosomes as surrogate markers of NETosis were significantly increased at admission and declined over 7 days. NETs were significantly associated with reduced hazards of clinical stability and hospital discharge in multivariate adjusted analyses. Moreover, NETs were associated with a 3.8-fold increased adjusted odds ratio of 30-day mortality. Prednisone treatment modified circulatory NET levels and was associated with beneficial outcome.CAP is accompanied by pronounced NET formation. Patients with elevated serum NET markers were at higher risk for clinical instability, prolonged length of hospital stay and 30-day all-cause mortality. NETs represent a novel marker for outcome and a possible target for adjunct treatments of pneumonia.
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Non-Celiac Gluten Sensitivity in patients with severe abdominal pain and bloating: The accuracy of ALCAT 5.
Di Stefano, M, Pesatori, EV, Manfredi, GF, De Amici, M, Grandi, G, Gabriele, A, Iozzi, D, Di Fede, G
Clinical nutrition ESPEN. 2018;:127-131
Abstract
BACKGROUND AND AIMS Non-Celiac Gluten Sensitivity (NCGS) is a recently proposed clinical condition causing both intestinal and extra-intestinal symptoms, without gastrointestinal lesions, which improve on avoiding gluten intake, in the absence of celiac disease and wheat allergy. The prevalence of this condition is still a matter of debate, in part due to the very recent introduction of an accepted diagnostic test, a double-blind, placebo controlled gluten challenge. However, this is a lengthy and cumbersome procedure, theoretically burdened by a significant reduction of patient compliance. ALCAT 5 is an automated in vitro test evaluating the toxic effect of gluten on neutrophils by the exposure of these cells to a gluten-containing extract of gluten-containing cereals. The test is very simple to perform, the results are rapidly obtained, and might represent, if sufficiently accurate, a promising alternative to diagnose gluten intolerance. The aim of this study was the comparison of ALCAT 5 results with those of a double-blind, placebo-controlled, gluten challenge, in a group of patients with clinically-suspected NCGS. METHODS Twenty-five patients (M/F 3/22, mean age 32 ± 4 yrs) with severe functional abdominal pain and bloating, who had previously undergone the ALCAT 5 test, were enrolled. All the subjects reported their symptoms on a gluten-containing diet and considered gluten the causal agent. Following the Salerno Experts' Criteria, they underwent a double-blind, placebo controlled trial with gluten vs placebo. A mean value during gluten ingestion >30% of the value during placebo was considered as indicative of gluten sensitivity. RESULTS After blinded administration of gluten, 13 out of 25 (52%) patients showed an increase in the severity of abdominal pain, and 11 out of 25 (44%) showed an increase in the severity of abdominal bloating. Considering these two symptoms together, in 16 patients out of 25 (64%), blinded gluten administration induced an increase of abdominal pain and/or bloating. The ALCAT 5 test proved to be positive in 20 and negative in 5 patients. In sixteen patients out of 25 the result of ALCAT 5 agreed with the double-blind trial (64%). In particular, both tests were positive in 14 patients and negative in 2. CONCLUSIONS In this subgroup of patients, ALCAT 5 could be used to support the clinical suspicion of the presence of NCGS and to address these patients to a blinded gluten challenge.