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1.
Innate immune remodeling by short-term intensive fasting.
Qian, J, Fang, Y, Yuan, N, Gao, X, Lv, Y, Zhao, C, Zhang, S, Li, Q, Li, L, Xu, L, et al
Aging cell. 2021;(11):e13507
Abstract
Previous studies have shown that long-term light or moderate fasting such as intermittent fasting can improve health and prolong lifespan. However, in humans short-term intensive fasting, a complete water-only fasting has little been studied. Here, we used multi-omics tools to evaluate the impact of short-term intensive fasting on immune function by comparison of the CD45+ leukocytes from the fasting subjects before and after 72-h fasting. Transcriptomic and proteomic profiling of CD45+ leukocytes revealed extensive expression changes, marked by higher gene upregulation than downregulation after fasting. Functional enrichment of differentially expressed genes and proteins exposed several pathways critical to metabolic and immune cell functions. Specifically, short-term intensive fasting enhanced autophagy levels through upregulation of key members involved in the upstream signals and within the autophagy machinery, whereas apoptosis was reduced by down-turning of apoptotic gene expression, thereby increasing the leukocyte viability. When focusing on specific leukocyte populations, peripheral neutrophils are noticeably increased by short-term intensive fasting. Finally, proteomic analysis of leukocytes showed that short-term intensive fasting not only increased neutrophil degranulation, but also increased cytokine secretion. Our results suggest that short-term intensive fasting boost immune function, in particular innate immune function, at least in part by remodeling leukocytes expression profile.
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Relationship Between Arteriovenous Fistula Stenosis and Circulating Levels of Neutrophil Granule Proteins in Chronic Hemodialysis Patients.
Oh, DJ, Lee, JH, Kwon, YE, Choi, HM
Annals of vascular surgery. 2021;:226-235
Abstract
BACKGROUND Arteriovenous fistula (AVF) stenosis leading to its failure is a major cause of morbidity in hemodialysis patients; however, detailed pathogenesis of AVF stenosis is still under investigation. To date, monocytes/macrophages have been considered pivotal players in chronic inflammation of vascular disease including atherosclerosis and AVF stenosis. However, recent evidence strongly suggests that neutrophils and neutrophil granule proteins are important contributors to vascular disease. The aim of the present study was to evaluate the relationship between AVF stenosis and neutrophil activation by measuring circulating levels of neutrophil elastase (NE) and lactoferrin, enzymes released on neutrophil activation, as well as other inflammation markers including neutrophil counts. METHODS This was a single-center, prospective observational study conducted on 83 prevalent hemodialysis patients with AVF. Blood levels of biomarkers and sonography (US) measurement were assessed at baseline and 1 year after enrollment. Clinical follow-up continued for one more year (a total of 2 years for each patient) to observe any AVF events. RESULTS Circulating levels of both NE and lactoferrin positively correlated with the degree of AVF stenosis. Patients with significant AVF stenosis had older AVFs, higher neutrophil-to-lymphocyte ratio (NLR), and higher circulating levels of NE and lactoferrin. On multivariate logistic regression analysis, both circulating levels of NE and NLR remained independent predictors of significant AVF stenosis. CONCLUSIONS Circulating levels of NE and the NLR were identified as independent predictors of at-risk AVF with significant stenosis. Our data suggest the potential role of neutrophil and innate immunity activation on the development of AVF stenosis.
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Novel Systemic Inflammation Markers to Predict COVID-19 Prognosis.
Karimi, A, Shobeiri, P, Kulasinghe, A, Rezaei, N
Frontiers in immunology. 2021;:741061
Abstract
Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic, challenging both the medical and scientific community for the development of novel vaccines and a greater understanding of the effects of the SARS-CoV-2 virus. COVID-19 has been associated with a pronounced and out-of-control inflammatory response. Studies have sought to understand the effects of inflammatory response markers to prognosticate the disease. Herein, we aimed to review the evidence of 11 groups of systemic inflammatory markers for risk-stratifying patients and prognosticating outcomes related to COVID-19. Numerous studies have demonstrated the effectiveness of neutrophil to lymphocyte ratio (NLR) in prognosticating patient outcomes, including but not limited to severe disease, hospitalization, intensive care unit (ICU) admission, intubation, and death. A few markers outperformed NLR in predicting outcomes, including 1) systemic immune-inflammation index (SII), 2) prognostic nutritional index (PNI), 3) C-reactive protein (CRP) to albumin ratio (CAR) and high-sensitivity CAR (hsCAR), and 4) CRP to prealbumin ratio (CPAR) and high-sensitivity CPAR (hsCPAR). However, there are a limited number of studies comparing NLR with these markers, and such conclusions require larger validation studies. Overall, the evidence suggests that most of the studied markers are able to predict COVID-19 prognosis, however NLR seems to be the most robust marker.
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4.
Mucin adsorbed by E. coli can affect neutrophil activation in vitro.
Mikhalchik, E, Balabushevich, N, Vakhrusheva, T, Sokolov, A, Baykova, J, Rakitina, D, Scherbakov, P, Gusev, S, Gusev, A, Kharaeva, Z, et al
FEBS open bio. 2020;(2):180-196
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Abstract
Bacteria colonizing human intestine adhere to the gut mucosa and avoid the innate immune system. We previously demonstrated that Escherichia coli isolates can adsorb mucin from a diluted solution in vitro. Here, we evaluated the effect of mucin adsorption by E. coli cells on neutrophil activation in vitro. Activation was evaluated based on the detection of reactive oxygen species production by a chemiluminescent reaction (ChL), observation of morphological alterations in neutrophils and detection of exocytosis of myeloperoxidase and lactoferrin. We report that mucin adsorbed by cells of SharL1 isolate from Crohn's disease patient's inflamed ileum suppressed the potential for the activation of neutrophils in whole blood. Also, the binding of plasma complement proteins and immunoglobulins to the bacteria was reduced. Desialylated mucin, despite having the same adsorption efficiency to bacteria, had no effect on the blood ChL response. The effect of mucin suggests that it shields epitopes that interact with neutrophils and plasma proteins on the bacterial outer membrane. Potential candidates for these epitopes were identified among the proteins within the bacterial outer membrane fraction by 2D-PAGE, fluorescent mucin binding on a blot and HPLC-MS/MS. In vitro, the following proteins demonstrated mucin adsorption: outer membrane porins (OmpA, OmpC, OmpD and OmpF), adhesin OmpX, the membrane assembly factor OmpW, cobalamine transporter, ferrum uptake protein and the elongation factor Ef Tu-1. In addition to their other functions, these proteins are known to be bacterial surface antigens. Therefore, the shielding of epitopes by mucin may affect the dynamics and intensity of an immune response.
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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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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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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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[Research advances in the role of neutrophil extracellular traps in childhood-onset systemic lupus erythematosus].
Li, L, Fu, HD
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2018;(3):251-254
Abstract
Neutrophil extracellular traps (NETs) represent a form of cell death distinct from apoptosis or necrosis. The imbalance between the formation and degradation of NETs has long been considered to be closely associated with the activity of autoimmune diseases such as systemic lupus erythematous (SLE). Reactive oxygen species derived from the nicotinamide adenine dinucleotide phosphate oxidase pathway or mitochondrial DNA pathway play a key role in the primary stage of NETs formation. The exposure or delayed degradation of abundant autoantigens, such as double-strand DNA, caused by abnormal activation of neutrophils can induce autoantibody to form immune complexes that deposit in local tissues and then induce the plasmacytoid dendritic cells to secrete the interferon alpha and other inflammatory factors. Those inflammatory factors will eventually cause endothelial cell injury. In order to provide a theoretical basis for targeted therapy and diagnosis of childhood-onset SLE, this paper reviews the role of NETs in the pathogenesis of SLE.