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RATIONALE: Research studies typically quantify acute respiratory exacerbation episodes (AECOPD) among people with chronic obstructive pulmonary disease (COPD) based on self-report elicited by survey questionnaire. However, AECOPD quantification by self-report could be inaccurate, potentially rendering it an imprecise tool for identification of those with exacerbation tendency. OBJECTIVE: Determine the agreement between self-reported and health records-documented quantification of AECOPD and their association with airway inflammation. METHODS: We administered a questionnaire to elicit the incidence and severity of respiratory exacerbations in the three years preceding the survey among current or former heavy smokers with or without diagnosis of COPD. We then examined electronic health records (EHR) of those with COPD and those without (tobacco-exposed persons with preserved spirometry or TEPS) to determine whether the documentation of the three-year incidence of moderate to very severe respiratory exacerbations was consistent with self-report using Kappa Interrater statistic. A subgroup of participants also underwent bronchoalveolar lavage (BAL) to quantify their airway inflammatory cells. We further used multivariable regressions analysis to estimate the association between respiratory exacerbations and BAL inflammatory cell composition with adjustment for covariates including age, sex, height, weight, smoking status (current versus former) and burden (pack-years). RESULTS: Overall, a total of 511 participants completed the questionnaire, from whom 487 had EHR available for review. Among the 222 participants with COPD (70 ± 7 years-old; 96% male; 70 ± 38 pack-years smoking; 42% current smoking), 57 (26%) reported having any moderate to very severe AECOPD (m/s-AECOPD) while 66 (30%) had EHR documentation of m/s-AECOPD. However, 42% of those with EHR-identified m/s-AECOPD had none by self-report, and 33% of those who reported m/s-AECOPD had none by EHR, suggesting only moderate agreement (Cohens Kappa = 0.47 ± 0.07; P

BACKGROUND: Endometriosis is considered as a systemic disease with the presence of proinflammatory cytokines in the circulation, which drives hypercoagulable state of endometriosis. Currently, endometriosis is classified into four stages: I (minimal), II (mild), III (moderate) and IV (severe). The aim of this study is to investigate the correlations between inflammatory markers and coagulation factors in patients diagnosed of endometriosis with stage IV. METHODS: This retrospective case-control study included 171 endometriosis patients with stage IV and 184 controls. Continuous data were expressed by mean ± standard deviation. Mann-Whitney U and χ2 tests were used to compare the medians and frequencies among the groups. Spearman analysis was conducted to determine the correlation among the measured parameters. The diagnostic values of the parameters differentiating endometriomas were tested by receiver operating characteristic (ROC) curve. RESULTS: The time of activated partial thromboplastin time (APTT) was decreased and the concentration of fibrinogen (FIB) and neutrophil-to-lymphocyte ratio (NLR) were increased in women of endometriosis with stage IV. The APTT were negatively correlated with NLR while the concentrations of FIB were positively correlated with NLR. The ROC analysis showed that the Area under the curve (AUC) of FIB was 0.766 (95% confidence interval:0.717-0.814) with sensitivity and specificity reaching 86.5 and 60.9%, respectively. The AUC of CA125 and CA199 was 0.638 (95% confidence interval: 0.578-0.697), 0.71 (95% confidence interval: 0.656-0.763) with sensitivity and specificity reaching 40.9 and 91.8%, 80.7 and 56.5% respectively. The combination of these factors showed the highest AUC of 0.895 (0.862-0.927) with sensitivity of 88.9% and specificity of 77.7%. CONCLUSION: In the present study, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV. Moreover, the coagulation factors combined with CA125 and CA199 were more reliable for identifying the endometriosis with stage IV.

Professional phagocytes like neutrophils and macrophages tightly control what they consume, how much they consume, and when they move after cargo uptake. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G protein subunit Gβ4 exhibited profound plasma membrane expansion, accompanied by marked reduction in plasma membrane tension. These biophysical changes promoted the phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. We also found that Gβ4-deficient neutrophils are defective in the normal inhibition of migration following cargo uptake. Sphingolipid synthesis played a central role in these phenotypes by driving plasma membrane accumulation in cells lacking Gβ4. In Gβ4 knockout mice, neutrophils not only exhibited enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. Together, these results reveal an unexpected, biophysical control mechanism central to myeloid functional decision-making.

UNLABELLED: Gonorrhea, caused by the bacterium Neisseria gonorrhoeae (Gc), is characterized by neutrophilic influx to infection sites. Gc has developed mechanisms to resist killing by neutrophils that include modifications to its surface lipooligosaccharide (LOS). One such LOS modification is sialylation: Gc sialylates its terminal LOS sugars with cytidine-5-monophosphate-N-acetylneuraminic acid, which is scavenged from the host using LOS sialyltransferase (Lst) since Gc cannot make its sialic acid. Sialylation enables sensitive strains of Gc to resist complement-mediated killing in a serum-dependent manner. However, little is known about the contribution of sialylation to complement-independent, direct Gc-neutrophil interactions. In the absence of complement, we found sialylated Gc expressing opacity-associated (Opa) proteins decreased the oxidative burst and granule exocytosis from primary human neutrophils. In addition, sialylated Opa+ Gc survived better than vehicle treated or Δlst Gc when challenged with neutrophils. However, Gc sialylation did not significantly affect Opa-dependent association with or internalization of Gc by neutrophils. Previous studies have implicated sialic acid-binding immunoglobulin-type lectins (Siglecs) in modulating neutrophil interactions with sialylated Gc. Blocking neutrophil Siglecs with antibodies that bind to their extracellular domains eliminated the ability of sialylated Opa+ Gc to suppress the oxidative burst and resist neutrophil killing. These findings highlight a new role for sialylation in Gc evasion of human innate immunity, with implications for the development of vaccines and therapeutics for gonorrhea. IMPORTANCE: Neisseria gonorrhoeae, the bacterium that causes gonorrhea, is an urgent global health concern due to increasing infection rates, widespread antibiotic resistance, and its ability to thwart protective immune responses. The mechanisms by which Gc subverts protective immune responses remain poorly characterized. One way N. gonorrhoeae evades human immunity is by adding sialic acid that is scavenged from the host onto its lipooligosaccharide, using the sialyltransferase Lst. Here, we found that sialylation enhances N. gonorrhoeae survival from neutrophil assault and inhibits neutrophil activation, independently of the complement system. Our results implicate bacterial binding of sialic acid-binding lectins (Siglecs) on the neutrophil surface, which dampens neutrophil antimicrobial responses. This work identifies a new role for sialylation in protecting N. gonorrhoeae from cellular innate immunity, which can be targeted to enhance the human immune response in gonorrhea.

It is well established that neutrophils adopt malleable polymorphonuclear shapes to migrate through narrow interstitial tissue spaces1-3. However, how polymorphonuclear structures are assembled remains unknown4. Here we show that in neutrophil progenitors, halting loop extrusion-a motor-powered process that generates DNA loops by pulling in chromatin5-leads to the assembly of polymorphonuclear genomes. Specifically, we found that in mononuclear neutrophil progenitors, acute depletion of the loop-extrusion loading factor nipped-B-like protein (NIPBL) induced the assembly of horseshoe, banded, ringed and hypersegmented nuclear structures and led to a reduction in nuclear volume, mirroring what is observed during the differentiation of neutrophils. Depletion of NIPBL also induced cell-cycle arrest, activated a neutrophil-specific gene program and conditioned a loss of interactions across topologically associating domains to generate a chromatin architecture that resembled that of differentiated neutrophils. Removing NIPBL resulted in enrichment for mega-loops and interchromosomal hubs that contain genes associated with neutrophil-specific enhancer repertoires and an inflammatory gene program. On the basis of these observations, we propose that in neutrophil progenitors, loop-extrusion programs produce lineage-specific chromatin architectures that permit the packing of chromosomes into geometrically confined lobular structures. Our data also provide a blueprint for the assembly of polymorphonuclear structures, and point to the possibility of engineering de novo nuclear shapes to facilitate the migration of effector cells in densely populated tumorigenic environments.

In sub-Saharan Africa, multidrug-resistant non-typhoidal Salmonella serovars are a common cause of fatal bloodstream infection. Malnutrition is a predisposing factor, but the underlying mechanisms are unknown. Here we show that vitamin A deficiency, one of the most prevalent micronutrient deficits afflicting African children, increases susceptibility to disseminated non-typhoidal Salmonella disease in mice and impairs terminal neutrophil maturation. Immature neutrophils had reduced expression of Slc11a1, a gene that encodes a metal ion transporter generally thought to restrict pathogen growth in macrophages. Adoptive transfer of SLC11A1-proficient neutrophils, but not SLC11A1-deficient neutrophils, reduced systemic Salmonella burden in Slc11a1-/- mice or mice with vitamin A deficiency. Loss of terminal granulopoiesis regulator CCAAT/enhancer-binding protein ϵ (C/EBPϵ) also decreased neutrophil-mediated control of Salmonella, but not that mediated by peritoneal macrophages. Susceptibility to infection increased in Cebpe-/- Slc11a1+/+ mice compared with wild-type controls, in an Slc11a1-expression-dependent manner. These data suggest that SLC11A1 deficiency impairs Salmonella control in part by blunting neutrophil-mediated defence.

PURPOSE: Evaluate the safety and efficacy of efbemalenograstim alfa for neutrophil support in breast cancer patients undergoing myelosuppressive chemotherapy in a phase 2, dose-finding, open-label study (NCT01648322, ClinicalTrials.gov, 2012-07-19). METHODS: 232 patients received up to 4 cycles of chemotherapy, 141 patients with docetaxel + cyclophosphamide (TC) and 91 patients with docetaxel + doxorubicin + cyclophosphamide (TAC). Patients were randomized to efbemalenograstim alfa (80, 240, or 320 µg/kg [TC]; 240 or 320 µg/kg [TAC]) or pegfilgrastim (6 mg) on Day 2 of each cycle. RESULTS: Efbemalenograstim alfa was non-inferior to pegfilgrastim in duration of moderate and severe neutropenia (absolute neutrophil count [ANC]  2.0 × 109/L after the expected ANC nadir) was 2.0-2.4 and 1.9 days for TAC patients treated with efbemalenograstim alfa and pegfilgrastim, respectively. No significant difference was found between any dose of efbemalenograstim alfa and pegfilgrastim in TAC Cycle 1 for incidence of moderate to severe neutropenia (76%-77% of patients) or incidence of severe neutropenia (ANC

BACKGROUND: Pulmonary hypertension (PH) in dogs with myxomatous mitral valve disease (MMVD) is caused by increased pulmonary venous pressure. Thrombosis, vascular remodeling, and vasoconstriction mediated by platelets could exacerbate PH. HYPOTHESIS: Dogs with PH will exhibit a hypercoagulable state, characterized by increased platelet activation, platelet-leukocyte, and platelet-neutrophil aggregate formation. ANIMALS: Eleven dogs (≥3.5 kg) diagnosed with MMVD and PH and 10 dogs with MMVD lacking PH. METHODS: Prospective cohort ex vivo study. All dogs underwent echocardiographic examination, CBC, 3-view thoracic radiographs, and heartworm antigen testing. Severity of PH and MMVD were assessed by echocardiography. Viscoelastic monitoring of coagulation was assessed using thromboelastography (TEG). Platelet activation and platelet-leukocyte/platelet-neutrophil interactions were assessed using flow cytometry. Plasma serotonin concentrations were measured by ELISA. RESULTS: Unstimulated platelets from dogs with MMVD and PH expressed more surface P-selectin than MMVD controls (P = .03). Platelets from dogs with MMVD and PH had persistent activation in response to agonists. The number of platelet-leukocyte aggregates was higher in dogs with MMVD and PH compared with MMVD controls (P = .01). Ex vivo stimulation of whole blood resulted in higher numbers of platelet-neutrophil aggregates in dogs with MMVD and PH (P = .01). Assessment of hypercoagulability based on TEG or plasma serotonin concentrations did not differ between groups. CONCLUSION AND CLINICAL IMPORTANCE: Platelet hyperresponsiveness and increased platelet-neutrophil interaction occur in dogs with MMVD and PH, suggesting that platelets play a role of in the pathogenesis of PH. Clinical benefits of antiplatelet drugs in dogs with MMVD and PH require further investigation.

BackgroundInfection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons that can have devastating consequences in the immunocompromised. In the immunocompetent individual, anti-parasitic effector mechanisms and a balanced immune response characterized by pro- and anti-inflammatory cytokine production establishes an asymptomatic infection that rarely leads to neurological symptoms. Several mechanisms are known to play a role in this successful immune response in the brain including T cell production of IFNγ and IL-10 and the involvement of CNS resident cells. This limitation of clinical neuropathology during chronic infection suggests a balance between immune response and neuroprotective mechanisms that collectively prevent clinical manifestations of disease. However, how these two vital mechanisms of protection interact during chronic Toxoplasma infection remains poorly understood.Main textThis study demonstrates a previously undescribed connection between innate neutrophils found chronically in the brain, termed "chronic brain neutrophils" (CBNeuts), and neuroprotective mechanisms during Toxoplasma infection. Lack of CBNeuts during chronic infection, accomplished via systemic neutrophil depletion, led to enhanced infection and deleterious effects on neuronal regeneration and repair mechanisms in the brain. Phenotypic and transcriptomic analysis of CBNeuts identified them as distinct from peripheral neutrophils and revealed two main subsets of CBNeuts that display heterogeneity towards both classical effector and neuroprotective functions in an age-dependent manner. Further phenotypic profiling defined expression of the neuroprotective molecules NRG-1 andErbB4 by these cells, and the importance of this signaling pathway during chronic infection was demonstrated via NRG-1 treatment studies.ConclusionsIn conclusion, this work identifies CBNeuts as a heterogenous population geared towards both classical immune responses and neuroprotection during chronic Toxoplasma infection and provides the foundation for future mechanistic studies of these cells.

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1β production is detrimental during Salmonella infection. Mice lacking IL-1β (IL-1β -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1β -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1β induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1β loss prevented mortality in Salmonella-infected IL-1β -/- mice. Finally, we found that IL-1β expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1β signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1β signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

While the involvement of actin polymerization in cell migration is well-established, much less is known about the role of transmembrane water flow in cell motility. Here, we investigate the role of water influx in a prototypical migrating cell, the neutrophil, which undergoes rapid, directed movement to sites of injury, and infection. Chemoattractant exposure both increases cell volume and potentiates migration, but the causal link between these processes are not known. We combine single-cell volume measurements and a genome-wide CRISPR screen to identify the regulators of chemoattractant-induced neutrophil swelling, including NHE1, AE2, PI3K-gamma, and CA2. Through NHE1 inhibition in primary human neutrophils, we show that cell swelling is both necessary and sufficient for the potentiation of migration following chemoattractant stimulation. Our data demonstrate that chemoattractant-driven cell swelling complements cytoskeletal rearrangements to enhance migration speed.

Research on neutrophil biology has been limited by the short life span and limited genetic manipulability of these cells, driving the need for representative and efficient model cell lines. The promyelocytic cell line HL-60 and its subline PLB-985 can be differentiated into neutrophil-like cells (NLCs) and have been used to study neutrophil functions including chemotaxis, phagocytosis, endocytosis, and degranulation. Compared to neutrophils derived from hematopoietic stem cells, NLCs serve as a cost-effective neutrophil model. NLCs derived from both HL-60 and PLB-985 cells have been shown to perform degranulation, an important neutrophil function. However, no study has directly compared the two lines as models for degranulation including their release of different types of mobilizable organelles. Furthermore, Nutridoma, a commercially available supplement, has recently been shown to improve the chemotaxis, phagocytosis, and oxidative burst abilities of NLCs derived from promyelocytic cells, however it is unknown whether this reagent also improves the degranulation ability of NLCs. Here, we show that NLCs derived from both HL-60 and PLB-985 cells are capable of degranulating, with each showing markers for the release of multiple types of secretory organelles, including primary granules. We also show that differentiating HL-60 cells using Nutridoma does not enhance their degranulation activity over NLCs differentiated using Dimethyl Sulfoxide (DMSO) plus Granulocyte-colony stimulating factor (G-CSF). Finally, we show that promyelocytic cells can be genetically engineered and differentiated using these methods, to yield NLCs with a defect in degranulation. Our results indicate that both cell lines serve as effective models for investigating the mechanisms of neutrophil degranulation, which can advance our understanding of the roles of neutrophils in inflammation and immunity.

ABSTRACT Introduction Methods Results Conclusions Estimating patient risk before heart surgery (HS) is crucial. Perioperative inflammation is associated with several complications and mortality. This study investigated blood cell count inflammatory indices (BCCII) to predict risks, including neutrophil‐to‐lymphocyte ratio (NLR), derivate NLR (DNLR), neutrophil‐to‐platelet‐lymphocyte ratio (NLPR), lymphocyte‐to‐monocyte ratio, platelet‐to‐lymphocyte ratio (PLR), Systemic Inflammatory Index (SII), Systemic Inflammatory Reaction Index (SIRI), and Aggregate Index of Systemic Inflammation (AISI).Data from a cohort of patients undergoing on‐pump HS at a single center in Brazil were retrospectively analyzed. Data were obtained from medical records and a laboratory analyzer, and SPSS version 20.0 was used for index calculations and statistical analyses.In total, 444 surgeries were performed, and 40 in‐hospital deaths occurred. Except for PLR, all other indexes were independent predictors of death after multivariate adjustment (all p < 0.05). Discrimination performance was absent for PLR and AISI, and NLR, NLPR, and DNLR demonstrated the best area under the receiver operating characteristic curve (AUC > 0.7; all p < 0.0001). For survivors (n = 404), all indexes exhibited a correlation with the length of hospital stay (all p < 0.03), and NLR, NLPR, and DNLR were predictors (p < 0.026) of poor operative outcomes (acute myocardial infarction, cerebrovascular attack, cardiac arrest, low cardiac output, prolonged mechanical ventilation, renal failure, and sepsis).All BCCII scores were associated with length of hospital stay. Apart from PLR, all indexes were independent predictors of in‐hospital mortality. Accuracy was highest for NLR, NLPR, and DNLR; for survivors, these three factors were good predictors of poor operative outcomes. [ABSTRACT FROM AUTHOR]

The article explores the potential of cell population data (CPD) as a diagnostic tool for distinguishing between venous thrombo-embolism (VTE), superficial vein thrombosis (SVT), and erysipelas. By analyzing CPD parameters in patients with these conditions, the study found differences in the intensity and type of cellular inflammation, with erysipelas showing more intense inflammation compared to DVT. The research suggests that CPD could be a promising tool for diagnosing VTE, but larger studies are needed to evaluate its true value in clinical practice. [Extracted from the article]

In patients with sepsis, neutrophil apoptosis tends to be inversely proportional to the severity of sepsis, but its mechanism is not yet clear. This study aimed to explore the mechanism of fatty acid binding protein 4 (FABP4) regulating neutrophil apoptosis through combined analysis of gut microbiota and short-chain fatty acids (SCFAs) metabolism. First, neutrophils from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced acute respiratory distress syndrome (ARDS) were purified and isolated RNA was applied for sequencing. Then, the cecal ligation and puncture (CLP) method was applied to induce the mouse sepsis model. After intervention with differential SCFAs sodium acetate, neutrophil apoptosis and FABP4 expression were further analyzed. Then, FABP4 inhibitor BMS309403 was used to treat neutrophils. We found CLP group had increased lung injury score, lung tissue wet/dry ratio, lung vascular permeability, and inflammatory factors IL-1β, TNF-α, IL-6, IFN-γ, and CCL3 levels in both bronchoalveolar lavage fluid and lung tissue. Additionally, FABP4 was lower in neutrophils of ARDS patients and mice. Meanwhile, CLP-induced dysbiosis of gut microbiota and changes in SCFAs levels were observed. Further verification showed that acetic acids reduced neutrophil apoptosis and FABP4 expression via FFAR2. Besides, FABP4 affected neutrophil apoptosis through endoplasmic reticulum (ER) stress, and neutrophil depletion alleviated the promotion of ARDS development by BMS309403. Moreover, FABP4 in neutrophils regulated the injury of RLE-6TN through inflammatory factors. In conclusion, FABP4 affected by gut microbiota-derived SCFAs delayed neutrophil apoptosis through ER stress, leading to increased inflammatory factors mediating lung epithelial cell damage. [ABSTRACT FROM AUTHOR]

The overactivated immune cells in the infectious lesion may lead to irreversible organ damages under severe infections. However, clinically used immunosuppressive anti‐inflammatory drugs will usually disturb immune homeostasis and conversely increase the risk of infections. Regulating the balance between anti‐inflammation and anti‐infection is thus critical in treating certain infectious diseases. Herein, considering that hydrogen peroxide (H2O2), myeloperoxidase (MPO), and neutrophils are upregulated in the inflammatory microenvironment and closely related to the severity of appendectomy patients, an inflammatory‐microenvironment‐responsive nanomedicine is designed by using poly(lactic‐co‐glycolic) acid (PLGA) nanoparticles to load chlorine E6 (Ce6), a photosensitizer, and luminal (Lum), a chemiluminescent agent. The obtained Lum/Ce6@PLGA nanoparticles, being non‐toxic within normal physiological environment, can generate cytotoxic single oxygen via bioluminescence resonance energy transfer (BRET) in the inflammatory microenvironment with upregulated H2O2 and MPO, simultaneously killing pathogens and excessive inflammatory immune cells in the lesion, without disturbing immune homeostasis. As evidenced in various clinically relevant bacterial infection models and virus‐induced pneumonia, Lum/Ce6@PLGA nanoparticles appeared to be rather effective in controlling both infection and inflammation, resulting in significantly improved animal survival. Therefore, the BRET‐based nanoparticles by simultaneously controlling infections and inflammation may be promising nano‐therapeutics for treatment of severe infectious diseases. [ABSTRACT FROM AUTHOR]

Neutrophils rapidly respond to inflammation resulting from infection, injury, and cancer. Intravital microscopy (IVM) has significantly advanced our understanding of neutrophil behavior, enabling real-time visualization of their migration, interactions with pathogens, and coordination of immune responses. This review delves into the insights provided by IVM studies on neutrophil dynamics in various inflammatory contexts. We also examine the dual role of neutrophils in tumor microenvironments, where they can either facilitate or hinder cancer progression. Finally, we highlight how computational modeling techniques, especially agent-based modeling, complement experimental data by elucidating neutrophil kinetics at the level of individual cells as well as their collective behavior. Understanding the role of neutrophils in health and disease is essential for developing new strategies for combating infection, inflammation and cancer. [ABSTRACT FROM AUTHOR]

Background: Neutrophils have long been consistently adjudged to hold a dominant position in acute inflammation, which once led people to undervalue their role in chronic malignancy. It is now acknowledged that neutrophils also infiltrate into the tumor microenvironment in substantial quantities and form a highly abundant immune population within the tumor, known as tumor-associated neutrophils (TANs). There has been a surge of interest in researching the eminent heterogeneity and plasticity of TANs in recent years, and scholars increasingly cotton on to the multifaceted functions of TANs so that strenuous endeavors have been devoted to enunciating their potential as therapeutic targets. Yet it remains much left to translate TAN-targeted immunotherapies into clinical practice. Therefore, there is great significance to comprehensively appraise the research status, focal point, and evolution trend of TAN by using bibliometric analysis. Methods: Publications related to TAN research from 2000 to 2024 are extracted from the Web of Science Core Collection. Bibliometric analysis and visualization were performed by tools encompassing Microsoft Excel, VOSviewer, CiteSpace, R-bibliometrix, and so on. Results: The bibliometric analysis included a total of 788 publications authored by 5291 scholars affiliated with 1000 institutions across 58 countries/regions, with relevant articles published in 324 journals. Despite China's maximum quantity of publications and top 10 institutions, the United States is the leading country with the most high-quality publications and is also the global cooperation center. FRONTIERS IN IMMUNOLOGY published the most papers, whereas CANCER RESEARCH is the highest co-cited journal. Israeli professor Fridlender, Zvi G. is the founder, pioneer, and cultivator with the highest citation counts and H-index in the TAN area. Our analysis prefigures the future trajectories: TAN heterogeneity, neutrophil extracellular trap, the crosstalk between TANs and immunocytes, and immunotherapy will likely be the focus of future research. Conclusion: A comprehensive bibliometric and visual analysis is first performed to map the current landscape and intellectual structure of TAN, which proffers fresh perspectives for further research. The accurate identification of distinct TAN subpopulations and the precise targeting of key pro-tumor/anti-tumor subpopulations hold immense potential to develop into a TAN-targeted immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Ewing Sarcoma (EWS) has been reported in seven children with Down syndrome (DS). To date, a detailed assessment of this solid tumour in DS patients is yet to be made. Methods: Here,we characterise a chemo-resistantmediastinal EWS in a 2-year-old DS child, the youngest ever reported case, by exploiting sequencing approaches. Results: The tumour showed a neuroectodermal development driven by the EWSR1-FLI1 fusion. The inherited myeloperoxidase deficiency of the patient caused failure of neutrophil-mediated cell death and promoted genomic instability. Discussion: In this context, the tumour underwent genome-wide near haploidisation resulting in a massive overexpression of pro-inflammatory cytokines. Recruitment of defective neutrophils fostered rapid evolution of this EWS. [ABSTRACT FROM AUTHOR]

Neutrophil polarization contributes to inflammation and its resolution, but the role of neutrophil polarization in myocardial ischemia/reperfusion (I/R) injury remains unknown. Cardiomyocytes (CMs) participate in cardiac inflammation by secreting extracellular vesicles (EVs). Therefore, we investigated the role of neutrophil polarization in myocardial I/R injury and the mechanism by which CM-derived EVs regulated neutrophil polarization. In the present study, our data showed that N1 neutrophil polarization enlarged cardiac infarct size and exacerbated cardiac dysfunction at the early stage of myocardial I/R. Further, CM-EV-derived miR-9-5p was identified as a mediator inducing neutrophils to the N1 phenotype. Mechanistically, miR-9-5p directly suppressed SOCS5 and SIRT1 expression, resulting in activating JAK2/STAT3 and NF-κB signaling pathways in neutrophils. Importantly, we confirmed that serum EV-derived miR-9-5p levels were independently associated with cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. These findings suggest neutrophil polarization is a promising therapeutic target against myocardial I/R-induced inflammation and injury, and serum EV-derived miR-9-5p is a promising prognostic biomarker for cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. [ABSTRACT FROM AUTHOR]

The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis‐induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single‐cell RNA sequencing (scRNA‐seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis‐associated ARDS and is positively correlated with disease severity. Mechanically, scRNA‐seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta‐1 (KPNB1), promoting abluminal‐to‐luminal neutrophil rTEM. Additionally, EC‐derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC‐derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis‐associated lung injury. [ABSTRACT FROM AUTHOR]

Epidural fibrosis is a primary contributor to the failure of laminectomy surgeries, leading to the development of failed back surgery syndrome (FBSS). Post-laminectomy, neutrophils infiltrate the surgical site, generating neutrophil extracellular traps (NETs) that contribute to epidural fibrosis. Reactive oxygen species (ROS) play a pivotal role in mediating NETs formation. Molecular hydrogen, recognized for its selective antioxidant properties and biosafety, emerges as a potential therapeutic gas in suppressing epidural fibrosis. In this study, we developed an in-situ hydrogen release hydrogel that inhibits the formation of NETs and mitigates epidural scarring. Biodegradable magnesium (Mg) microspheres served as a hydrogen source, coated with PLGA to regulate hydrogen release. These microspheres (Mg@PLGA) were then incorporated into a PLGA-PEG-PLGA thermosensitive hydrogel (Mg@PLGA@Gel), providing a surgical implant for sustained, long-term hydrogen release. In vitro experiments confirmed the biocompatibility of the system, demonstrating that hydrogen produced by Mg@PLGA effectively neutralizes neutrophil intracellular ROS and inhibits NETs formation. Histological analyses, including H&E staining, MRI, Masson staining, and immunohistochemistry, collectively indicate that Mg@PLGA@Gel is biocompatible and effectively inhibits epidural fibrosis post-laminectomy. Furthermore, Mg@PLGA@Gel inhibits ROS accumulation and NETs formation at the surgical site. These findings suggest that Mg@PLGA@Gel ensures continuous, therapeutic hydrogen concentration, providing relief from epidural fibrosis in a laminectomy mouse model. • The hydrogen-releasing hydrogel combines the therapeutic effects of a physical barrier with immunomodulation. • In situ-generated molecular hydrogen scavenges ROS caused by surgical stress and suppresses NETs formation. • The hydrogen-releasing hydrogel is demonstrated to exhibit high biocompatibility and inhibit epidural scar formation in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

Post-tuberculosis (post-TB) lung disease is increasingly recognized as a major contributor to the global burden of chronic lung disease, with recent estimates indicating that over half of TB survivors have impaired lung function after successful completion of TB treatment. However, the pathologic mechanisms that contribute to post-TB lung disease are not well understood, thus limiting the development of therapeutic interventions to improve long-term outcomes after TB. This report summarizes the work of the Pathogenesis and Risk Factors Committee for the Second International Post-Tuberculosis Symposium, which took place in Stellenbosch, South Africa, in April 2023. The committee first identified six areas with high translational potential: 1) tissue matrix destruction, including the role of matrix metalloproteinase dysregulation and neutrophil activity; 2) fibroblasts and profibrotic activity; 3) granuloma fate and cell death pathways; 4) mycobacterial factors, including pathogen burden; 5) animal models; and 6) the impact of key clinical risk factors, including HIV, diabetes, smoking, malnutrition, and alcohol. We share the key findings from a literature review of those areas, highlighting knowledge gaps and areas where further research is needed. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) effectively kills cancer cells and initiates immune responses that promote anticancer effects locally and systemically. Primarily developed for local and regional cancers, the potential of PDT for systemic antitumor effects [in situ photo‐vaccination (ISPV)] remains underexplored. This study investigates: (1) the comparative effectiveness of paclitaxel (PTX) prodrug [Pc‐(L‐PTX)2] for PDT and site‐specific PTX effects versus its pseudo‐prodrug [Pc‐(NCL‐PTX)2] for PDT combined with checkpoint inhibitors; (2) mechanisms driving systemic antitumor effects; and (3) the prophylactic impact on preventing cancer recurrence. A bilateral tumor model was established in BALB/c mice through subcutaneous injection of CT26 cells. Mice received the PTX prodrug (0.5 μmole kg−1, i.v.), and tumors were treated with a 690‐nm laser (75 mW cm−2 for 30 min, drug‐light interval 0.5 h, light does 135 J cm−1), followed by anti‐CTLA‐4 (100 μg dose−1, i.p.) on days 1, 4, and 7. Notable enhancement in both local and systemic antitumor effectiveness was observed with [Pc‐(L‐PTX)2] compared to [Pc‐(NCL‐PTX)2] with checkpoint inhibitor. Immune cell depletion and immunohistochemistry confirmed neutrophils and CD8+ T cells are effectors for systemic antitumor effects. Treatment‐induced immune memory resisted newly rechallenged CT26, showcasing prophylactic benefits. ISPV with a PTX prodrug and anti‐CTLA‐4 is a promising approach for treating metastatic cancers and preventing recurrence. [ABSTRACT FROM AUTHOR]

Background: Severe adenovirus pneumonia in children has a high mortality rate, but research on risk prediction models is lacking. Such models are essential as they allow individualized predictions and assess whether children will likely progress to severe disease. Methods: A retrospective analysis was performed on children with adenovirus pneumonia who were hospitalized at the Children's Hospital of Nanjing Medical University from January 2017 to March 2024. The patients were grouped according to clinical factors, and the groups were compared using Ridge regression and multiple logistic regression to identify risk factors associated with severe adenovirus pneumonia. A prediction model was constructed, and its value in clinical application was evaluated. Results: 699 patients were included in the study, with 284 in the severe group and 415 in the general group. Through the screening of 44 variables, the final risk factors for severe adenovirus pneumonia in children as the levels of neutrophils (OR = 1.086, 95% CI: 1.054‒1.119, P < 0.001), D-dimer (OR = 1.005, 95% CI: 1.003‒1.007, P < 0.001), fibrinogen degradation products (OR = 1.341, 95% CI: 1.034‒1.738, P = 0.027), B cells (OR = 1.076, 95%CI: 1.046‒1.107, P < 0.001), and lactate dehydrogenase (OR = 1.008, 95% CI: 1.005‒1.011, P < 0.001). The value of the area under the receiver operating characteristic curve was 0.974, the 95% CI was 0.963–0.985, and the P-value of the Hosmer-Lemeshow test was 0.547 (P > 0.05), indicating that the model had strong predictive power. Conclusion: In this study, the clinical variables of children with adenovirus pneumonia were retrospectively analyzed to identify risk factors for severe disease. A prediction model for severe disease was constructed and evaluated, showing good application value. [ABSTRACT FROM AUTHOR]

As frontline cells, the precise recruitment of neutrophils is crucial for resolving inflammation and maintaining the homeostasis of the organism. Increasing evidence suggests the pivotal role of neutrophil chemotaxis in cancer progression and metastasis. Here, we collected clinical data and peripheral blood samples from patients with tumours to examine the alterations in the neutrophil quantity and chemotactic function using the Cell Chemotaxis Analysis Platform (CCAP). Transcriptome sequencing data of pan-cancer were obtained from The Cancer Genome Atlas (TCGA). Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, we selected a total of 29 genes from 155 neutrophil- and chemotaxis-related genes to construct the ChemoScore model. Meanwhile, nomogram-based comprehensive model was established for clinical application. Furthermore, immunofluorescence (IF) staining was employed to assess the relationship between the neutrophils infiltrating and the survival outcomes of tumours. In this observational study, the chemotactic function of neutrophils was notably diminished in patients. The establishment and validation of ChemoScore suggested neutrophil chemotaxis to be a risk factor in most tumours, whereby higher scores were associated with poorer survival outcomes and were correlated with various immune cells and malignant biological processes. Moreover, IF staining of tumour tissue substantiated the adverse correlation between neutrophil infiltration and the survival of patients with lung adenocarcinoma (P = 0.0002) and colon adenocarcinoma (P = 0.0472). Taken together, patients with tumours demonstrated a decrease in chemotactic function. ChemoScore potentially prognosticates the survival of patients with tumours. Neutrophil chemotaxis provides novel directions and theoretical foundations for anti-tumour treatment. [ABSTRACT FROM AUTHOR]

Summary We investigated the effect of Ropeginterferon alfa‐2b (Ropeg) versus phlebotomy‐only (Phl‐O) on the neutrophil‐to‐lymphocyte ratio (NLR) in 126 patients randomized in the low‐polycythaemia vera (PV) phase II trial. Patients with a baseline NLR ≥3.5 vs. <3.5 had a longer history of PV, were more likely to have splenomegaly, higher JAK2V617F variant allele frequency (VAF) (56% vs. 20% p = 0.001) and more proliferative disease. Ropeg was superior to Phl‐O in reducing NLR (p = 0.008), and the reduction was strongly influenced by the reduction in neutrophils and less by a change in lymphocytes (−59% and −14% respectively). This effect was associated with the achievement of the low‐PV primary end‐point (p = 0.021), symptom reduction and reduction in JAK2 VAF. Interestingly, the reduction in JAK2 VAF from baseline was linearly associated with the reduction in NLR. Patients who failed Phl‐O at 12 months had characteristics that distinguished them from responders, including very high NLR and resistance to cross‐over to 100 μg Ropeg every 2 weeks suggesting higher escalated doses of Ropeg. In conclusion, the study provides evidence that NLR can serve as a valuable biomarker to assess and guide treatment with Ropeg in the early stage of low‐risk PV patients. [ABSTRACT FROM AUTHOR]

Neutrophils collectively migrate to sites of injury and infection. How these swarms are coordinated to ensure the proper level of recruitment is unknown. Using an ex vivo model of infection, we show that human neutrophil swarming is organized by multiple pulsatile chemoattractant waves. These waves propagate through active relay in which stimulated neutrophils trigger their neighbors to release additional swarming cues. Unlike canonical active relays, we find these waves to be self-terminating, limiting the spatial range of cell recruitment. We identify an NADPH-oxidase-based negative feedback loop that is needed for this self-terminating behavior. We observe near-constant levels of neutrophil recruitment over a wide range of starting conditions, revealing surprising robustness in the swarming process. This homeostatic control is achieved by larger and more numerous swarming waves at lower cell densities. We link defective wave termination to a broken recruitment homeostat in the context of human chronic granulomatous disease. [Display omitted] • Neutrophil swarming is organized by pulsatile, self-extinguishing waves of LTB4 • NADPH-oxidase activation is critical for relay wave self-extinction • Neutrophils adjust the size and number of waves to homeostatically control recruitment • Chronic granulomatosis disease neutrophils generate undamped relay waves that do not extinguish Strickland et al. find that human neutrophils organize pulsatile, self-extinguishing waves of leukotriene B4 to ensure robust homeostatic recruitment. Self-extinguishing waves are dependent on the activity of NADPH oxidase, and deficiency in this pathway leads to a reduced ability to extinguish relay waves. [ABSTRACT FROM AUTHOR]

Although the role of low-density granulocytes (LDGs), neutrophils in the peripheral blood mononuclear cell (PBMC) fraction, and neutrophil extracellular traps (NETs) in assessing lupus disease severity is acknowledged, data specific to childhood-onset lupus remains scarce. This study analyzed 46 patients with childhood-onset systemic lupus erythematosus (82.6% females, mean age 14.5 ± 0.3 years), including 26 cases with normal complement levels and 20 with low complement levels, along with 20 healthy adult volunteers. Key parameters that distinguished healthy volunteers from lupus patients and differentiated between lupus patients with low and normal complement were serum interferon (IFN)-α, serum citrullinated histone 3 (CitH3), and extracellular traps (ETs) in LDGs. However, NETs (assessed by nuclear staining morphology), LDG abundance, and other parameters (such as endotoxemia, cytokines, and double-stranded (ds) DNA) did not show such differentiation. When lipopolysaccharide (LPS) was administered to LDGs in the PBMC fraction, it induced ETs in both low and normal complement groups, indicating the inducible nature of ETs. In adult healthy volunteers, activation by recombinant IFN-α or dsDNA in isolated neutrophils induced LDGs and NETs (identified using immunofluorescent staining for CitH3, myeloperoxidase, and neutrophil elastase) at 45 min and 3 h post-stimulation, respectively. Additionally, approximately half of the LDGs underwent late apoptosis at 3 h post-stimulation, as determined by flow cytometry analysis. Activation by IFN-α or dsDNA in LDGs also led to a more pronounced expression of CD66b, an adhesion molecule, compared to regular-density neutrophils, suggesting higher activity in LDGs. In conclusion, IFN-α and/or dsDNA in serum may transform regular-density neutrophils into LDGs before progressing to NETosis and apoptosis, potentially exacerbating lupus severity through cell death-induced self-antigens. Therefore, LDGs and ETs in LDGs could provide deeper insights into the pathophysiology of childhood-onset lupus. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions. Author summary: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a significant global health issue. Neutrophils, immune cells that rapidly enter the lungs during Mtb infection, contribute both to fighting the infection and exacerbating lung damage. Their metabolic state, especially the way they produce energy, is crucial for their function during TB. However, the specific impact of Mtb on neutrophil metabolism and its role in TB progression has been unclear. In this study, we investigated the roles of glycolysis and fatty acid metabolism in neutrophil responses to Mtb infection. We found that inhibiting glycolysis worsens TB outcomes, while blocking fatty acid oxidation (FAO) provides protection, reducing lung damage, bacterial load, and overall disease severity. Notably, FAO inhibition specifically disrupts the accumulation of an immature neutrophil population that is more susceptible to Mtb, thereby improving infection control. Targeting carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in fatty acid metabolism, impaired neutrophil migration to infection sites and enhanced their antimicrobial activity. These findings suggest that modulating neutrophil metabolism, particularly through FAO inhibition, could be a promising strategy for developing host-directed TB therapies. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) continues to be a major health concern in today's world. Despite conflictive findings, evidence supports systemic inflammation's impact on CRC patients' survival rates. Therefore, this study aims to assess the prognostic role of the innate immune system in patients with CRC. Method: A total of 449 patients were included, with a 5-year follow-up period, and absolute neutrophil counts and their related ratios were measured. Results: The non-survival group had increased levels of white blood cells, neutrophils (both p<0.001), and monocytes (p=0.038), compared to the survival group, along with other neutrophil-related ratios. We observed increased mortality risk in patients in the highest tertile of white blood cells [HR=1.85 (1.09-3.13), p<0.05], neutrophils [HR=1.78 (95% CI: 1.07-2.96), p<0.05], and monocytes [HR=2.11 (95% CI: 1.22-3.63)], compared to the lowest tertile, after adjusting for all clinicopathological variables. Random forest analysis identified neutrophils as the most crucial variable in predicting survival rates, having an AUC of 0.712, considering all clinicopathological variables. A positive relationship between neutrophil counts and metastasis was observed when neutrophil counts are considered continuous (b=0.92 (0.41), p<0.05) and tumor size (width) when neutrophils were considered as logistic variable (T1 vs T3) [OR=1.42, (95% CI: 1.05-1.98), p<0.05]. Conclusion: This study offers comprehensive insights into the immune factors that impact the prognosis of CRC, emphasizing the need for personalized prognostic tools. [ABSTRACT FROM AUTHOR]

Background: Proteinuria is a key indicator of kidney damage in diabetic nephropathy, and its severity correlates with the progression of the disease. In diabetic patients, it is crucial to identify reliable predictors for proteinuria and its severity for early detection and management of kidney damage. Materials and Methods: This cross-sectional study was conducted from November 16, 2022, to May 20, 2023, on patients with type 2 diabetes mellitus (T2DM) who were outpatients at clinics of Shahid Modarres Hospital, Tehran, Iran. Participants were categorized based on their level of proteinuria during 24-h as follows: group A1 (normal to mildly increased proteinuria), Group A2 (moderately increased proteinuria), and Group A3 (severely increased proteinuria). Then, complete blood cell count and other laboratory parameters, were compared between study groups. Results: In this cross-sectional study, 128 participants, including 53 (41.4%) men and 75 (58.6%) women with T2DM, were enrolled. The mean age of participants was 56.40 ± 13.31 years. Although there were no significant differences between cell count and parameters of three groups, a statistically significant difference was seen in neutrophil-to-lymphocyte ratio (NLR) (1.93 ± 0.76, 2.34 ± 0.93, and 2.73 ± 1.07 in A1, A2, and A3 groups, respectively; P = 0.003). Further analysis showed that NLR was significantly higher in Group A3 compared to A1 (2.73 ± 1.07 vs. 1.93 ± 0.76, respectively; P = 0.006), but there was no significant difference between Groups A3 and A2 (2.73 ± 1.07 vs. 2.34 ± 0.93, respectively; P = 0.482) and between Groups A2 and A1 (2.34 ± 0.93 vs. 1.93 ± 0.76, respectively; P = 0.257). Conclusion: Overall, this study suggests that some routine laboratory parameters may be associated with proteinuria and its severity in patients with T2DM. NLR, in particular, showed this association in our study, promising future studies evaluating this association and whether it can help as a predictor or not. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of Araucaria sp. brown propolis (ABP) against trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Methods: Animals received vehicle (1% DMSO, 1 ml/kg) or hydroalcoholic extract of ABP (hydroalcoholic extract of Araucaria sp. brown propolis (HEABP), 30, 100, and 300 mg/kg) orally, or dexamethasone (25 mg/kg, s.c.) for 5 days. On day 4, the animals received intracolonic TNBS (150 mg/kg), on day 6 they were euthanized. The weight of the animals, the macroscopic and microscopic colonic damage, reduced glutathione (GSH) and malondialdehyde (MDA) levels, and the activity of glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) were measured in colon homogenate. The action of HEABP and two isolated compounds in neutrophil migration was recorded. Key findings: HEABP (100 and 300 mg/kg), but not dexamethasone, decreased colonic lesion, and increased colonic mucin staining. In parallel, HEABP decreased MDA and restored GSH levels and the activity of SOD, CAT, and GST in the colon. A dose-dependent inhibition of MPO activity was observed (LogIC50 = 1.9). Moreover, HEBPA and the junicedric and abietic acids inhibited the neutrophil chemotaxis in vitro and HEBPA reduced neutrophil migration in vivo. Conclusion: HEABP may be promising in the therapies for inflammatory bowel diseases, reducing oxidative and inflammatory damage, especially mediated by neutrophils. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 can have long-lasting effects, but the effects on blood parameters and inflammation are poorly understood. The aim of this study was to evaluate morphological and inflammatory markers in long-term COVID-19 patients. Aim: To evaluate complete blood count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and morphology in mild versus severe long COVID-19. Material and methods: In total, 39 long COVID-19 patients were stratified into mild (n = 25) and severe (n = 14) groups. Blood counts, NLR, PLR were measured. Cell morphology was analysed. ROC curves were used to determine biomarker thresholds. Survival was assessed using Kaplan-Meier curves. Results and discussion: Severe patients had lower leukocytes but higher neutrophils, indicating greater inflammation. NLR and PLR were significantly increased in severe patients compared to mild patients (NLR 12 vs 8; PLR 140 vs 100). NLR and PLR were higher than in controls, confirming their utility as inflammatory markers. NLR and PLR effectively discriminated between mild and severe disease. High NLR and PLR predicted poorer prognosis. Altered leukocyte morphology such as cytoplasmic vacuolization correlated with severity. Conclusions: NLR and PLR are promising biomarkers for assessing severity of long COVID-19, while morphological changes in blood cells provide additional evidence of inflammation. Further studies in larger populations are warranted. [ABSTRACT FROM AUTHOR]

Aseptic pustulosis involves inflammatory skin conditions with nonbacterial pustules on erythema, accompanied by neutrophil and eosinophil infiltration in the epidermis. Dysregulation of the interleukin (IL)-36 pathway leads to neutrophil aggregation and pustule formation. Variants in IL36RN , CARD14 , AP1S3 , MPO , SERPINA3 and BTN3A3 have been identified in generalized pustular psoriasis (GPP) in the past. Some patients with acrodermatitis continua of Hallopeau (ACH), palmoplantar pustulosis and acute generalized exanthematous pustulosis (AGEP) also exhibit mutations in IL36RN , CARD14 and AP1S3 , albeit with regional and population-specific variations. This study aims to explore a shared genetic foundation among those with aseptic pustulosis. We performed Sanger sequencing on six genes in 126 patients with aseptic pustulosis. Genetic analysis identified IL36RN variants strongly associated with ACH, AGEP and subcorneal pustular dermatosis (SPD). Immunohistochemistry revealed elevated inflammatory cytokines in all subtypes. This study establishes a significant association between IL36RN variants and ACH, AGEP and SPD, emphasizing the IL-1/IL-36–chemokine–neutrophil axis as a common pathogenic mechanism. Targeting this axis holds promise for therapeutic interventions for aseptic pustulosis. [ABSTRACT FROM AUTHOR]

Neutrophils, the most abundant white blood cells in the human circulation, play crucial roles in various diseases, including kidney disease. Traditionally viewed as short-lived pro-inflammatory phagocytes that release reactive oxygen species, cytokines and neutrophil extracellular traps, recent studies have revealed their complexity and heterogeneity, thereby challenging this perception. Neutrophils are now recognized as transcriptionally active cells capable of proliferation and reverse migration, displaying phenotypic and functional heterogeneity. They respond to a wide range of signals and deploy various cargo to influence the activity of other cells in the circulation and in tissues. They can regulate the behavior of multiple immune cell types, exhibit innate immune memory, and contribute to both acute and chronic inflammatory responses while also promoting inflammation resolution in a context-dependent manner. Here, we explore the origin and heterogeneity of neutrophils, their functional diversity, and the cues that regulate their effector functions. We also examine their emerging role in infectious and non-infectious diseases with a particular emphasis on kidney disease. Understanding the complex behavior of neutrophils during tissue injury and inflammation may provide novel insights, thereby paving the way for potential therapeutic strategies to manage acute and chronic conditions. By deciphering their multifaceted role, targeted interventions can be developed to address the intricacies of neutrophil-mediated immune responses and improve disease outcomes. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is an acute liver disease with a high mortality rate in clinical practice, characterized histologically by extensive hepatocellular necrosis and massive neutrophil infiltration. However, the role of these abnormally infiltrating neutrophils during ALF development is unclear. Here, in an ALF mouse model, metabolites were identified that promote the formation of neutrophil extracellular traps (NETs) in the liver, subsequently influencing macrophage differentiation and disease progression. ALF occurs with abnormalities in hepatic and intestinal metabolites. Abnormal metabolites (LTD4 and glutathione) can directly, or indirectly via reactive oxygen species, promote NET formation of infiltrating neutrophils, which subsequently regulate macrophages in a pro‐inflammatory M1‐like state, inducing an amplification of the destructive effects of inflammation. Together, this study provides new insights into the role of NETs in the pathogenesis of ALF. [ABSTRACT FROM AUTHOR]

Psoriasis is an inflammatory skin disease with various symptoms of differing severities and with the reported prominent involvement of neutrophil extracellular traps (NETs). The excitation of neutrophils, e.g., by interleukin 8 (IL-8) or lipopolysaccharide (LPS), leads to the citrullination of histones and the release of protein–DNA complexes into the extracellular space, where they are digested by DNases. Our aim was to explore data on the levels of protein-complexed DNAs neutrophil elastase–DNA (NE-DNA) and myeloperoxidase–DNA (MPO-DNA), citrullinated histones (citH2, citH3, citH4), and NET-degrading enzyme DNase I in the serum of psoriatic patients with varying severities of clinical symptoms assessed with the Psoriasis Area Severity Index (PASI), Body Surface Area (BSA), and Dermatology Life Quality Index (DLQI) scores. The levels of factors were detected in 52 patients with psoriasis and 22 healthy volunteers by the enzyme-linked immunosorbent assay (ELISA). The results showed the elevated levels of NE-DNA, MPO-DNA, citH3, and DNase I in the patients with psoriasis compared to healthy volunteers (p < 0.05). Additionally, changes were noticed in the levels of NE-DNA, citH3, and DNase I, depending on the severity of symptoms (p < 0.05). In mild psoriasis (PASI < 10, BSA < 10, DLQI < 10), the suppressing activity of the enzyme caused the impaired ability to remove the physiological level of NETs, whereas in moderate to severe psoriasis (PASI ≥ 10, BSA ≥ 10, DLQI ≥ 10), the enhanced activity of DNase I failed to remove NETs due to the observed overexpression. It may, thus, be concluded that the mechanism of action of NETs, which play an undeniable role in psoriatic diseases, seem to follow two different paths depending on the severity of disease, which may be crucial in selecting potential anti-NET treatment methods. [ABSTRACT FROM AUTHOR]

Neutrophil dysfunction is a form of immune suppression in patients with β-thalassemia (Beta-thal), although data on this are limited. In this study, blood from patients and healthy volunteers was analyzed. Flow cytometry analysis demonstrated an increase in immature neutrophils (CD16− CD62L+) and aged (senescent) neutrophils (CD16+ CD62L−) in Beta-thal patients compared to healthy volunteers. The Beta-thal neutrophils demonstrated less prominent chemotaxis and phagocytosis than healthy neutrophils at the baseline. With phorbol myristate acetate (PMA) or lipopolysaccharide (LPS) stimulations, some of the indicators, including the flow cytometry markers (CD11b, CD62L, CD66b, CD63, apoptosis, and reactive oxygen species) and neutrophil extracellular traps (NETs; detected by anti-citrullinated histone 3 immunofluorescence), were lower than the control. Additionally, low-density neutrophils (LDNs), which are found in the peripheral blood mononuclear cell (PBMC) fraction, were observed in Beta-thal patients but not in the control group. The expression of CD11b, CD66b, CD63, arginase I, and ROS in LDNs was higher than the regular normal-density neutrophils (NDNs). The proliferation rate of CD3+ T cells isolated from the PBMC fraction of healthy volunteers was higher than that of the cells from patients with Beta-thal. The incubation of red blood cell (RBC) lysate plus ferric ions with healthy NDNs transformed the NDNs into the aged neutrophils (decreased CD62L) and LDNs. In conclusion, iron overload induces neutrophil diversity along with some dysfunctions. [ABSTRACT FROM AUTHOR]

Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), are increasingly common and present significant healthcare challenges. Neutrophil extracellular traps (NETs), chromatin fibers expulsed by neutrophil granulocytes, can promote immunotherapy resistance via an impairment of CD8+ T cell-mediated cytotoxicity. Here, to identify a potential therapeutic target, we investigate the expulsion of NETs and their relation to CD8+ T cell infiltration in NMSC. Immunofluorescence staining for neutrophils (CD15) and NETs (H3cit), as well as immunohistochemistry for cytotoxic T cells (CD8+) on human cSCCs (n = 24), BCCs (n = 17) and MCCs (n = 12), revealed a correlation between neutrophil infiltration and ulceration diameter in BCC and MCC, but not in cSCC. In BCC and cSCC, neutrophil infiltration also correlated with the cross-sectional area (CSA). NETs were not associated with established risk factors but with the presence of an ulceration, and, in cSCC, with abscess-like structures. CD8+ T cell infiltration was not reduced in tumors that were NET-positive nor in those with a denser neutrophil infiltration. This study is the first to report and characterize NETs in NMSC. Thus, it gives an incentive for further research in this relevant yet understudied topic. [ABSTRACT FROM AUTHOR]

Simple Summary: Daratumumab (DARA) plus bortezomib, thalidomide, and dexamethasone (D-VTd) represent the standard of induction care in Europe for autologous stem cell transplantation (auto-SCT)-eligible, newly diagnosed multiple myeloma (NDMM) patients. This study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after auto-SCT. Our findings indicate that patients treated with D-VTd experienced longer neutrophil and platelet engraftment times than those treated with VTd. Additionally, D-VTd treatment was associated with a higher incidence of febrile neutropenia and grade 2 or higher diarrhea. However, no significant differences were observed in the median number of days to discharge. The conclusion we can draw from our real-life study is that a four-drug induction therapy containing DARA does not impact transplant safety outcomes. Background: This real-life study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after autologous stem cell transplantation (auto-SCT). Methods: Sixty consecutive NDMM patients received four cycles of induction therapy with D-VTd. The conditioning regimen consisted of melphalan 200 mg/m2. These patients were compared with a historical control group of 80 patients who received four cycles of VTd as induction therapy. Results: The median days to reach neutrophil and platelet engraftment significantly differed between patients treated with D-VTd (11 and 13 days, respectively) and VTd (10 and 12 days). Univariate Cox analyses show that patients treated with D-VTd had a hazard ratio of neutrophil engraftment that was 42% significantly lower than those in the VTd arm (HR: 0.58, p = 0.002), and a multivariate model confirmed this result. Patients treated with D-VTd developed FN more frequently. Univariate and multivariate logistic regressions revealed an association between D-VTd and FN. Delayed engraftment did not correlate with more extended hospitalization. No patients died in the first six months after transplantation. Conclusions: Our real-life study showed that a four-drug induction therapy containing DARA does not impact transplant safety outcomes. [ABSTRACT FROM AUTHOR]

Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2‐congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC‐II) region from TB‐susceptible H2j mice transferred onto the genetic background of the TB‐resistant C57BL/6 (H2b) strain. Susceptible B6.I‐9.3 mice differ from B6 progenitors by the alleles of their only classical MHC‐II H2‐Aβ gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB‐related phenotypes between mice of the two strains and (ii) decipher interactions between the H2‐Aβ and S100A8/9 genes. Here, we describe the dynamics of TB‐related phenotypes differentiating B6.I‐9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4+ T‐cell population, an enlarged S100A8/9‐positive neutrophil population and higher S100A8/9 serum levels in B6.I‐9.3 mice collectively form the 'susceptible' phenotype before infection. An increase in IL‐17 and a decrease in intrferon‐gamma production by CD4+ T‐cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9‐producing neutrophils in lungs and spleens and the proportion of Th17 CD4+ T‐cells in lungs are significantly lower in the presence of the MHC‐II dominant 'resistant' b allele compared to the recessive 'susceptible' j/j genotype. This provides direct genetic evidence that MHC‐II‐regulated CD4+ T‐cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity. [ABSTRACT FROM AUTHOR]

Background and Objective Methods Results Conclusion Severe asthma is a heterogeneous disease with subtype classification according to dominant airway infiltrates, including eosinophilic (Type 2 high), or non‐eosinophilic asthma. Non‐eosinophilic asthma is further divided into paucigranulocytic or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in the airways. Severe non‐eosinophilic asthma has few effective treatments and many patients do not qualify for biologic therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease and has proven a valuable therapeutic target. We hypothesized that the CFTR may also play a role in non‐eosinophilic asthma.Patient‐derived human bronchial epithelial cells (hBECs) were isolated and differentiated at the air‐liquid interface. Single cell RNA‐sequencing (scRNAseq) was used to identify epithelial cell subtypes and transcriptional activity. Ion transport was investigated with Ussing chambers and immunofluorescent quantification of ionocyte abundance in human airway epithelial cells and murine models of asthma.We identified that hBECs from patients with non‐eosinophilic asthma had reduced CFTR function, and did not differentiate into CFTR‐expressing ionocytes compared to those from eosinophilic asthma or healthy donors. Similarly, ionocytes were also diminished in the airways of a murine model of neutrophilic‐dominant but not eosinophilic asthma. Treatment of hBECs from healthy donors with a neutrophilic asthma‐like inflammatory cytokine mixture led to a reduction in ionocytes.Inflammation‐induced loss of CFTR‐expressing ionocytes in airway cells from non‐eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target. [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) is characterized by inflammatory attacks due to overactivation of pyrin inflammasome. This study aimed to investigate the reliability of S100A8/A9, neopterin, and matrix metalloproteinase 3 (MMP3) at monitoring subclinical inflammation and disease activity, and at differentiating FMF attacks from appendicitis, the most common misdiagnosis among FMF patients. Blood samples (n = 75), comprising from FMF patients during an attack (n = 20), the same FMF patients during the attack-free period (n = 14), patients with appendicitis (n = 24), and healthy volunteers (n = 17) were obtained. Duplicate determinations of S100A8/A9, neopterin, and MMP-3 levels were conducted using the enzyme-linked immunosorbent assay (ELISA). FMF patients with and without attack and patients with appendicitis had significantly elevated S100A8/A9 levels compared to healthy volunteers (P-values: < 0.001, 0.036, 0.002, respectively). Patients with appendicitis and FMF patients with and without attack had significantly increased serum neopterin levels compared to healthy volunteers (P-value: < 0.001). MMP3 levels were significantly higher among patients with appendicitis and FMF patients during attack compared to healthy controls (P-values: < 0.001, 0.001). Serum levels of S100A8/A9, neopterin, and MMP3 were increased significantly during attacks compared to attack-free periods among FMF patients (P-values: 0.03, 0.047, 0.007). S100A8/A9 emerges as a valuable marker for monitoring disease activity. Neopterin and S100A8/A9 might help physicians to monitor subclinical inflammation during the attack-free periods of FMF patients. MMP3 might aid in diagnosing FMF attacks when distinguishing between attack and attack-free periods is challenging. S100A8/A9 emerges as a valuable marker for monitoring disease activity. Neopterin and S100A8/A9 might help physicians to monitor subclinical inflammation during the attack-free periods of FMF patients. MMP3 might aid in diagnosing FMF attacks when distinguishing between attack and attack-free periods is challenging. Graphical Abstract [ABSTRACT FROM AUTHOR]

Introduction: Triple‐ and quad‐refractory multiple myeloma patients usually have an aggressive course and a poor prognosis. Available therapeutic options are scarce. Methods: The objective of the current study was to evaluate responses and toxicities of VDTPACE or mCBAD with hematopoietic stem‐cell support as a bridge to subsequent therapies in patients with refractory/relapsed multiple myeloma. Results: Thirteen patients were included (11 mCBAD, 2 VDTPACE), and 21 cycles of chemotherapy with hematopoietic stem‐cell support were delivered. Mean number of previous therapies was 4.8. Stem cells were infused on a median day 9.9 after chemotherapy. Mean time to neutrophil recovery was 18.2 days in patients receiving the first cycle and 15.9 following subsequent cycles. Before therapy, most patients were in PD (77%), PR (15%), or VGPR (8%). Following treatment, the best responses achieved were PR (46%), VGPR (46%), and CR (8%). Median overall and progression‐free survivals were 17 and 9 months. There has been no case of non‐relapse mortality. In the 21 cycles, the main complications were infectious. Conclusion: Intensive chemotherapy can decrease disease burden in patients with relapsed/refractory MM, and stem‐cell support can successfully decrease toxicities and treatment‐related mortality associated with these regimens and may be a good bridging option. [ABSTRACT FROM AUTHOR]

Objectives: The gingival mucosal barrier, an important oral cavity barrier, plays a significant role in preventing pathogenic microorganism invasion and maintaining periodontal tissue health. Pathogenic microorganism invasion of the gingival mucosa produces a large number of cytokines. Among them, pyroptosis is an important player in exacerbating immune‐inflammatory responses, leading to tissue destruction. However, the mechanism of pyroptosis and the immune response it triggers have not been fully elucidated. We provide an overview of recent advances in understanding gingival physical barrier pyroptosis and inflammation‐induced hyperimmunity. Methods: PubMed, Web of Science databases were searched for articles, reviews, and clinical studies published until March 2024. Results: We summarised the importance of the gingival barrier in terms of the functions of different cells, described the progress in research on gingival epithelial cell and gingival fibroblast pyroptosis and the immune‐inflammatory response it induces, and discussed the relationship between pyroptosis and systemic diseases, association of multiple cell death systems. Finally, we propose future directions for pyroptosis research. Conclusions: Pyroptosis often triggers a range of inflammatory immune responses that lead to associated diseases. Therefore, further study of the molecular mechanisms of pyroptosis and the immune responses is warranted. [ABSTRACT FROM AUTHOR]

Objectives: Tumor‐associated neutrophils (TANs) are among the most abundant inflammatory cells in tumor microenvironment (TME). Aldehyde dehydrogenase 3A1 (ALDH3A1) is significantly reduced in oral squamous cell carcinoma (OSCC), ALDH3A1 overexpression suppresses tumorigenesis by inhibiting inflammation. This study investigated the relationship and mechanisms underlying the crosstalk between ALDH3A1 and TANs in OSCC. Materials and Methods: Immunohistochemistry and immunofluorescence were performed to investigate the abundance of TANs and the expression of ALDH3A1. dHL‐60 were induced with tumor‐conditioned media and recombinant IL‐6/IL‐8. The expression of key proteins in PI3K/AKT/NF‐κB pathway were detected by RT‐PCR and western blot. A xenograft model was utilized to examine the effect of ALDH3A1 on tumorigenicity and polarization of TANs. Results: In patients with OSCC, TANs significantly increased and were associated with a worse prognosis. Additionally, ALDH3A1 negatively correlated with TANs infiltration and especially the N2 phenotype which was the prominent part in OSCC. Furthermore, our study demonstrated that tumor‐derived IL‐8 drives ALDH3A1‐mediated TANs N2 polarization in the TME through PI3K/AKT/NF‐κB pathway in vitro and in vivo. Conclusion: Our results indicate that TANs can serve as a prognostic biomarker and ALDH3A1 could be a promising therapeutic target for regulating TANs N2 polarization in antitumor therapy. [ABSTRACT FROM AUTHOR]

Objective: Midpalatal expansion (MPE) is routinely employed to treat transverse maxillary arch deficiency. Neutrophils are indispensable for recruiting bone marrow stromal cells (BMSCs) at the initial stage of bone regeneration. This study aimed to explore whether neutrophils participate in MPE and how they function during bone formation under mechanical stretching. Materials and Methods: The presence and phenotype of neutrophils in the midpalatal suture during expansion were detected by flow cytometry and immunofluorescence staining. The possible mechanism of neutrophil recruitment and polarization was explored in vitro by exposing vascular endothelial cells (VECs) to cyclic tensile strain. Results: The number of neutrophils in the distracted suture peaked on Day 3, and N2‐type neutrophils significantly increased on Day 5 after force application. The depletion of circulatory neutrophils reduced bone volume by 43.6% after 7‐day expansion. The stretched VECs recruited neutrophils via a CXCR2 mechanism in vitro, which then promoted BMSC osteogenic differentiation through the VEGFA/VEGFR2 axis. Consistently, these neutrophils showed higher expression of canonical N2 phenotype genes, including CD206 and Arg1. Conclusions: These results suggested that neutrophils participated in early bone formation during MPE. Based on these findings, we propose that stretched VECs recruited and polarized neutrophils, which, in turn, induced BMSC osteogenic differentiation. [ABSTRACT FROM AUTHOR]

The article discusses the role of the chemokine CCL28 in modulating neutrophil responses during infection with mucosal pathogens. The study found that CCL28 promotes neutrophil accumulation in the gut during Salmonella infection and in the lung during Acinetobacter infection. Neutrophils isolated from the infected mucosa express CCL28 receptors on their surface, and CCL28 stimulation enhances neutrophil antimicrobial activity. The absence of CCL28 in mice confers protection against Acinetobacter infection but makes them susceptible to Salmonella infection. These findings highlight the importance of CCL28 in the immune response to bacterial infections. The document also provides information on the materials and methods used in the study, as well as references to related scientific articles. [Extracted from the article]

Objectives Systemic lupus erythematosus (SLE) is a complex autoimmune disease with varying symptoms and multi-organ damage. Relapse-remission cycles often persist for many patients for years with the current treatment. Improved understanding of molecular changes caused by SLE flare and intensive treatment may result in more targeted therapies. Methods RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 65 SLE patients in flare, collected both before (SLE1) and after (SLE2) in-hospital treatment, along with 15 healthy controls (HC). Differentially expressed genes (DEGs) were identified among the three groups. Enriched functions and key molecular signatures of the DEGs were analysed and scored to elucidate the transcriptomic changes during treatment. Results Few upregulated genes in SLE1 vs HC were affected by treatment (SLE2 vs SLE1), mostly functional in interferon signalling (IFN), plasmablasts and neutrophils. IFN and plasmablast signatures were repressed, but the neutrophil signature remained unchanged or enhanced by treatment. The IFN and neutrophil scores together stratified the SLE samples. IFN scores correlated well with leukopenia, while neutrophil scores reflected relative cell compositions but not cell counts. Conclusions In-hospital treatment significantly relieved SLE symptoms with expression changes of a small subset of genes. Notably, IFN signature changes matched SLE flare and improvement, while enhanced neutrophil signature upon treatment suggested the involvement of low-density granulocytes (LDG) in disease development. [ABSTRACT FROM AUTHOR]