New roles for immune cells, overcoming the classical cytotoxic response, have been highlighted by growing evidence. The immune cells, such as neutrophils, monocytes/macrophages, and eosinophils, are versatile cells involved in the release of web-like DNA structures called extracellular traps (ETs) which represent a relevant mechanism by which these cells prevent microbes' dissemination. In this process, many enzymes, such as elastase, myeloperoxidase (MPO), and microbicidal nuclear and granule proteins, which contribute to the clearance of entrapped microorganisms after DNA binding, are involved. However, an overproduction and release of ETs can cause unwanted and dangerous effects in the host, resulting in several pathological manifestations, among which are chronic inflammatory disorders, autoimmune diseases, cancer, and diabetes. In this review, we discuss the release mechanisms and the double-edged sword role of ETs both in physiological and in pathological contexts. In addition, we evaluated some possible strategies to target ETs aimed at either preventing their formation or degrading existing ones.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the main cause of hospitalization and death of patients with chronic obstructive pulmonary disease. This is largely due to bacterial resistance caused by clinical antibiotic abuse and the limited efficacy of current treatment strategies in managing noninfectious AECOPD, which presents a significant challenge for clinicians. Therefore, it is urgent for clinical treatment and prevention of AECOPD to fully understand the specific mechanism of AECOPD in the immune system and master the key differences between infectious factors and noninfectious factors. This article systematically discusses AECOPD triggered by various factors, including the activation of immune system, the recruitment and activation of inflammatory cells and the role of specific inflammatory responses, and through a comprehensive review of the literature, this article expounds the existing targeted diagnosis and treatment methods and technologies at different stages in order to provide new ideas and strategies for clinical prevention and treatment of AECOPD.

Much of the fatality of tumors is linked to the growth of metastases, which can emerge months to years after apparently successful treatment of primary tumors. Metastases arise from disseminated tumor cells (DTCs), which disperse through the body in a dormant state to seed distant sites. While some DTCs lodge in pre-metastatic niches (PMNs) and rapidly develop into metastases, other DTCs settle in distinct microenvironments that maintain them in a dormant state. Subsequent awakening, induced by changes in the microenvironment of the DTC, causes outgrowth of metastases. Hence, there has been extensive investigation of the factors causing survival and subsequent awakening of DTCs, with the goal of disrupting these processes to decrease cancer lethality. We here provide a detailed overview of recent developments in understanding of the factors controlling dormancy and awakening in the lung, a common site of metastasis for many solid tumors. These factors include dynamic interactions between DTCs and diverse epithelial, mesenchymal, and immune cell populations resident in the lung. Paradoxically, among key triggers for metastatic outgrowth, lung tissue remodeling arising from damage induced by the treatment of primary tumors play a significant role. In addition, growing evidence emphasizes roles for inflammation and aging in opposing the factors that maintain dormancy. Finally, we discuss strategies being developed or employed to reduce the risk of metastatic recurrence.

As a global public health issue, childhood maltreatment is associated with significant morbidity and mortality. We aimed to investigate the association between childhood maltreatment and immune-mediated inflammatory disorders (IMIDs).

We conducted a retrospective matched open cohort study using a UK primary care database between January 1, 1995 and January 31, 2021. Clinical codes were used to identify patients exposed to childhood maltreatment who were matched by general practice (GP), age, and sex to up to four unexposed patients. Cox regression analysis was used to evaluate the risk of developing IMIDs (inflammatory bowel disease, coeliac disease, rheumatoid arthritis, psoriasis, multiple sclerosis, systemic lupus erythematosus) during follow-up in the exposed versus unexposed groups.

256,130 exposed patients were matched to 712,478 unexposed patients. Those exposed to childhood maltreatment were 1) at an increased risk of developing Rheumatoid arthritis (aHR 1·39; 95 % CI 1·12-1·74) and Psoriasis (aHR 1·16; 95 % CI 1·10-1·23), 2) not statistically significantly at risk of developing inflammatory bowel disease (aHR 0·87; 95 % CI 0·75-1·00), multiple sclerosis (aHR 1·07; 95 % CI 0·77-1·49) and systemic lupus erythematosus (aHR 1·28; 95 % CI 0·89-1·85) and 3) at a reduced risk of coeliac disease (aHR 0·74; 95 % CI 0·62-0·88) compared to the unexposed group.

Childhood maltreatment is estimated to affect one in three children globally; therefore, an increased risk of developing rheumatoid arthritis and psoriasis represents a substantial contribution to the burden of IMIDs. Implementation of broad public health approaches to prevent and detect childhood maltreatment and its negative downstream consequences, such as, IMID development, is essential.

Exposure to cigarette smoke significantly enhances susceptibility to bacterial infections by inducing physiological and structural alterations, including immune system dysregulation. This exposure also augments bacterial virulence including biofilm formation, leading to severe infectious diseases and antibiotic resistance. Notably, cigarette smoke exposure increases the incidence of pneumonia by up to 2.5-fold and tuberculosis by up to 4.1-fold. Nicotine, a primary constituent of cigarette smoke, has been extensively characterized for its immunomodulatory effects. However, despite the wealth of knowledge on nicotine's impact on the host immune response, there is a paucity of data regarding its direct effects on various pulmonary pathogens. In the present review, we discuss the main findings in this field.

Cardiovascular diseases (CVDs) continue to pose a significant burden on global health, prominently contributing to morbidity and mortality rates worldwide. Recent years have witnessed an increasing recognition of the intricate involvement of neutrophil extracellular traps (NETs) in the pathology of diverse cardiovascular conditions. This review provides a comprehensive analysis of the multifaceted functions of NETs in cardiovascular diseases, shedding light on the impact on atherosclerosis, myocardial infarction, heart failure, myocarditis, atrial fibrillation, aortic stenosis, and the potential therapeutic avenues targeting NETs.

Neutrophil extracellular traps (NETs), crucial in immune defense mechanisms, are renowned for their propensity to expel decondensed chromatin embedded with inflammatory proteins. Our comprehension of NETs in pathogen clearance, immune regulation and disease pathogenesis, has grown significantly in recent years. NETs are not only pivotal in the context of infections but also exhibit significant involvement in sterile inflammation. Evidence suggests that excessive accumulation of NETs can result in vessel occlusion, tissue damage, and prolonged inflammatory responses, thereby contributing to the progression and exacerbation of various pathological states. Nevertheless, NETs exhibit dual functionalities in certain pathological contexts. While NETs may act as autoantigens, aggregated NET complexes can function as inflammatory mediators by degrading proinflammatory cytokines and chemokines. The delineation of molecules and signaling pathways governing NET formation aids in refining our appreciation of NETs' role in immune homeostasis, inflammation, autoimmune diseases, metabolic dysregulation, and cancer. In this comprehensive review, we delve into the multifaceted roles of NETs in both homeostasis and disease, whilst discussing their potential as therapeutic targets. Our aim is to enhance the understanding of the intricate functions of NETs across the spectrum from physiology to pathology.

Recent genome-wide association studies (GWAS) have revealed shared genetic components among alcohol, opioid, tobacco and cannabis use disorders. However, the extent of the underlying shared causal variants and effector genes, along with their cellular context, remain unclear. We leveraged our existing 3D genomic datasets comprising high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq and RNA-seq across >50 diverse human cell types to focus on genomic regions that coincide with GWAS loci. Using stratified LD regression, we determined the proportion of genomewide SNP heritability attributable to the features assayed across our cell types by integrating recent GWAS summary statistics for the relevant traits: alcohol use disorder (AUD), tobacco use disorder (TUD), opioid use disorder (OUD) and cannabis use disorder (CanUD). Statistically significant enrichments (P<0.05) were observed in 14 specific cell types, with heritability reaching 9.2-fold for iPSC-derived cortical neurons and neural progenitors, confirming that they are crucial cell types for further functional exploration. Additionally, several pancreatic cell types, notably pancreatic beta cells, showed enrichment for TUD, with heritability enrichments up to 4.8-fold, suggesting genomic overlap with metabolic processes. Further investigation revealed significant positive genetic correlations between T2D with both TUD and CanUD (FDR<0.05) and a significant negative genetic correlation with AUD. Interestingly, after partitioning the heritability for each cell type's cis-regulatory elements, the correlation between T2D and TUD for pancreatic beta cells was greater (r=0.2) than the global genetic correlation value. Our study provides new genomic insights into substance use disorders and implicates cell types where functional follow-up studies could reveal causal variant-gene mechanisms underpinning these disorders.

Neutrophils are a crucial component of the innate immune system and play a pivotal role in various physiological processes. From a physical perspective, hitchhiking is considered a phenomenon of efficient transportation. The combination of neutrophils and hitchhikers has given rise to effective delivery systems both in vivo and in vitro, thus neutrophils hitchhiking become a novel approach to disease treatment. This article provides an overview of the innovative and feasible application of neutrophils as drug carriers. It explores the mechanisms underlying neutrophil function, elucidates the mechanism of drug delivery mediated by neutrophil-hitchhiking, and discusses the potential applications of this strategy in the treatment of cancer, immune diseases, inflammatory diseases, and other medical conditions.

Cocaine-use disorder (CUD) has been associated with early life adversity and activated cellular immune responses. Women are most vulnerable to complications from chronic substance disorders, generally presenting an intense feeling of abstinence and consuming significant drug amounts. Here, we investigated neutrophil functional activities in CUD, including the formation of neutrophil extracellular traps (NETs) and related intracellular signalling. We also investigated the role of early life stress in inflammatory profiles.

Blood samples, clinical data, and history of childhood abuse or neglect were collected at the onset of detoxification treatment of 41 female individuals with CUD and 31 healthy controls (HCs). Plasma cytokines, neutrophil phagocytosis, NETs, intracellular reactive oxygen species (ROS) generation, and phosphorylated protein kinase B (Akt) and mitogen-activated protein kinases (MAPK)s were assessed by flow cytometry.

CUD subjects had higher scores of childhood trauma than controls. Increased plasma cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-12, and IL-10), neutrophil phagocytosis, and production of NETs were reported in CUD subjects as compared to HC. Neutrophils of CUD subjects also produced high levels of intracellular ROS and had more activated Akt and MAPKs (p38/ERK), which are essential signalling pathways involved in cell survival and NETs production. Childhood trauma scores were significantly associated with neutrophil activation and peripheral inflammation.

Our study reinforces that smoked cocaine and early life stress activate neutrophils in an inflammatory environment.

Our ability to interrogate the tumor immune microenvironment (TIME) at an ever-increasing granularity has uncovered critical determinants of disease progression. Not only do we now have a better understanding of the immune response in breast cancer, but it is becoming possible to leverage key mechanisms to effectively combat this disease. Almost every component of the immune system plays a role in enabling or inhibiting breast tumor growth. Building on early seminal work showing the involvement of T cells and macrophages in controlling breast cancer progression and metastasis, single-cell genomics and spatial proteomics approaches have recently expanded our view of the TIME. In this article, we provide a detailed description of the immune response against breast cancer and examine its heterogeneity in disease subtypes. We discuss preclinical models that enable dissecting the mechanisms responsible for tumor clearance or immune evasion and draw parallels and distinctions between human disease and murine counterparts. Last, as the cancer immunology field is moving toward the analysis of the TIME at the cellular and spatial levels, we highlight key studies that revealed previously unappreciated complexity in breast cancer using these technologies. Taken together, this article summarizes what is known in breast cancer immunology through the lens of translational research and identifies future directions to improve clinical outcomes.

Neutrophils, accounting for ≈70% of human peripheral leukocytes, are key cells countering bacterial and fungal infections. Neutrophil homeostasis involves a balance between cell maturation, migration, aging, and eventual death. Neutrophils undergo different death pathways depending on their interactions with microbes and external environmental cues. Neutrophil death has significant physiological implications and leads to distinct immunological outcomes. This review discusses the multifarious neutrophil death pathways, including apoptosis, NETosis, pyroptosis, necroptosis, and ferroptosis, and outlines their effects on immune responses and disease progression. Understanding the multifaceted aspects of neutrophil death, the intersections among signaling pathways and ramifications of immunity will help facilitate the development of novel therapeutic methods.

Neutrophils are the first line of defense against pathogens. They are divided into multiple subpopulations during development and kill pathogens through various mechanisms. Neutrophils are considered one of the markers of severe COVID-19.

In-depth research has revealed that neutrophil subpopulations have multiple complex functions. Different subsets of neutrophils play an important role in the progression of COVID-19.

In this review, we provide a detailed overview of the developmental processes of neutrophils at different stages and their recruitment and activation after SARS-CoV-2 infection, aiming to elucidate the changes in neutrophil subpopulations, characteristics, and functions after infection and provide a reference for mechanistic research on neutrophil subpopulations in the context of SARS-CoV-2 infection. In addition, we have also summarized research progress on potential targeted drugs for neutrophil immunotherapy, hoping to provide information that aids the development of therapeutic drugs for the clinical treatment of critically ill COVID-19 patients.

Neutrophils have both antimicrobial ability and pathogenic effect in the immune system, neutrophil extracellular traps (NETs) formation is one of the representative behaviors of their dual role. NETs formation was triggered by pathogen-related components and pathogen non-related proteins as cytokines to exert its effector functions. Recent studies indicate that the pathogenicity of NETs contributed to several skin diseases such as psoriasis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and neutrophilic dermatosis. Especially in neutrophilic dermatosis, a heterogeneous group of inflammatory skin disorders characterized with sterile neutrophilic infiltrate on dermis, NETs formation was reported as the way of participation of neutrophils in the pathogenesis of these diseases. In this review, we describe the different processes of NETs formation, then summarized the most recent updates about the pathogenesis of neutrophilic dermatosis and the participation of NETs, including pyoderma gangrenosum and PAPA syndrome, Behçet syndrome, hidradenitis suppurativa, Sweet Syndrome, pustular dermatosis and other neutrophilic dermatosis. Furthermore, we discuss the link between NETs formation and the development of neutrophilic dermatosis.

Tobacco smoking generates airway inflammation in chronic obstructive pulmonary disease (COPD), and its involvement in the development of lung cancer is still among the leading causes of early death. Therefore, we aimed to have a better understanding of the disbalance in immunoregulation in chronic inflammatory conditions in smoker subjects with stable COPD (stCOPD), exacerbating COPD (exCOPD), or non-small cell lung cancer (NSCLC).

Smoker controls without chronic illness were recruited as controls. Through extensive mapping of single cells, surface receptor quantification was achieved by single-cell mass cytometry (CyTOF) with 29 antibodies. The CyTOF characterized 14 main immune subsets such as CD4+, CD8+, CD4+/CD8+, CD4-/CD8-, and γ/δ T cells and other subsets such as CD4+ or CD8+ NKT cells, NK cells, B cells, plasmablasts, monocytes, CD11cdim, mDCs, and pDCs. The CD4+ central memory (CM) T cells (CD4+/CD45RA-/CD45RO+/CD197+) and CD4+ effector memory (EM) T cells (CD4+/CD45RA-/CD45RO+/CD197-) were FACS-sorted for RNA-Seq analysis. Plasma samples were assayed by Luminex MAGPIX® for the quantitative measurement of 17 soluble immuno-oncology mediators (BTLA, CD28, CD80, CD27, CD40, CD86, CTLA-4, GITR, GITRL, HVEM, ICOS, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, TLR-2) in the four studied groups.

Our focus was on T-cell-dependent differences in COPD and NSCLC, where peripheral CD4+ central memory and CD4+ effector memory cells showed a significant reduction in exCOPD and CD4+ CM showed elevation in NSCLC. The transcriptome analysis delineated a perfect correlation of differentially expressed genes between exacerbating COPD and NSCLC-derived peripheral CD4+ CM or CD4+ EM cells. The measurement of 17 immuno-oncology soluble mediators revealed a disease-associated phenotype in the peripheral blood of stCOPD, exCOPD, and NSCLC patients.

The applied single-cell mass cytometry, the whole transcriptome profiling of peripheral CD4+ memory cells, and the quantification of 17 plasma mediators provided complex data that may contribute to the understanding of the disbalance in immune homeostasis generated or sustained by tobacco smoking in COPD and NSCLC.

Smoking is a serious global health issue. Cigarette smoking contains over 7000 different chemicals. The main harmful components include nicotine, acrolein, aromatic hydrocarbons and heavy metals, which play the key role for cigarette-induced inflammation and carcinogenesis. Growing evidences show that cigarette smoking and its components exert a remarkable impact on regulation of immunity and dysregulated immunity promotes inflammation and cancer. Therefore, this comprehensive and up-to-date review covers four interrelated topics, including cigarette smoking, inflammation, cancer and immune system. The known harmful chemicals from cigarette smoking were summarized. Importantly, we discussed in depth the impact of cigarette smoking on the formation of inflammatory or tumor microenvironment, primarily by affecting immune effector cells, such as macrophages, neutrophils, and T lymphocytes. Furthermore, the main molecular mechanisms by which cigarette smoking induces inflammation and cancer, including changes in epigenetics, DNA damage and others were further summarized. This article will contribute to a better understanding of the impact of cigarette smoking on inducing inflammation and cancer.

Pancreatitis is an inflammatory disease, which is triggered by adverse events in acinar cells of the pancreas. After the initial injury, infiltration of neutrophils in pancreas is observed. In the initial stages of pancreatitis, the inflammation is sterile. It has been shown that the presence of neutrophils at the injury site can modulate the disease. Their depletion in experimental animal models of the acute pancreatitis has been shown to be protective. But information on mechanism of contribution to inflammation by neutrophils at the injury site is not clear. Once at injury site, activated neutrophils release azurophilic granules containing proteolytic enzymes and generate hypochlorous acid which is a strong microbicidal agent. Additionally, emerging evidence shows that neutrophil extracellular traps (NETs) are formed which consist of decondensed DNA decorated with histones, proteases and granular and cytosolic proteins. NETs are considered mechanical traps for microbes, but there is preliminary evidence to indicate that NETs, which constitute a special mechanism of the neutrophil defence system, play an adverse role in pancreatitis by contributing to the pancreatic inflammation and distant organ injury. This review presents the overall current information about neutrophils and their role including NETs in acute pancreatitis (AP). It also highlights current gaps in knowledge which should be explored to fully elucidate the role of neutrophils in AP and for therapeutic gains.

Over 1.1 billion people smoke worldwide. The alkaloid nicotine is a prominent and addictive component of tobacco. In addition to tumors and cardiovascular disorders, tobacco consumption is associated with a variety of chronic-inflammatory diseases. Although neutrophilic granulocytes (neutrophils) play a role in the pathogenesis of many of these diseases, the impact of nicotine on neutrophils has not been systematically reviewed so far.

The aim of this systematic review was to evaluate the direct influence of nicotine on human neutrophil functions, specifically on cell death/damage, apoptosis, chemotaxis, general motility, adhesion molecule expression, eicosanoid synthesis, cytokine/chemokine expression, formation of neutrophil extracellular traps (NETs), phagocytosis, generation of reactive oxygen species (ROS), net antimicrobial activity, and enzyme release.

This review was conducted according to the PRISMA guidelines. A literature search was performed in the databases NCBI Pubmed® and Web of Science™ in February 2023. Inclusion criteria comprised English written research articles, showing in vitro studies on the direct impact of nicotine on specified human neutrophil functions.

Of the 532 originally identified articles, data from 34 articles were finally compiled after several evaluation steps. The considered studies highly varied in methodological aspects. While at high concentrations (>3 mmol/l) nicotine started to be cytotoxic to neutrophils, concentrations typically achieved in blood of smokers (in the nmol/l range) applied for long exposure times (24-72h) supported the survival of neutrophils. Smoking-relevant nicotine concentrations also increased the chemotaxis of neutrophils towards several chemoattractants, elevated their production of elastase, lipocalin-2, CXCL8, leukotriene B4 and prostaglandin E2, and reduced their integrin expression. Moreover, while nicotine impaired the neutrophil phagocytotic and anti-microbial activity, a range of studies demonstrated increased NET formation. However, conflicting effects were found on ROS generation, selectin expression and release of β-glucuronidase and myeloperoxidase.

Nicotine seems to support the presence in the tissue and the inflammatory and selected tissue-damaging activity of neutrophils and reduces their antimicrobial functions, suggesting a direct contribution of nicotine to the pathogenesis of chronic-inflammatory diseases via influencing the neutrophil biology.

The peptide toxin candidalysin, secreted by Candida albicans hyphae, promotes stimulation of neutrophil extracellular traps (NETs). However, candidalysin alone triggers a distinct mechanism for NET-like structures (NLS), which are more compact and less fibrous than canonical NETs. Candidalysin activates NADPH oxidase and calcium influx, with both processes contributing to morphological changes in neutrophils resulting in NLS formation. NLS are induced by leucotoxic hypercitrullination, which is governed by calcium-induced protein arginine deaminase 4 activation and initiation of intracellular signalling events in a dose- and time-dependent manner. However, activation of signalling by candidalysin does not suffice to trigger downstream events essential for NET formation, as demonstrated by lack of lamin A/C phosphorylation, an event required for activation of cyclin-dependent kinases that are crucial for NET release. Candidalysin-triggered NLS demonstrate anti-Candida activity, which is resistant to nuclease treatment and dependent on the deprivation of Zn2+ . This study reveals that C. albicans hyphae releasing candidalysin concurrently trigger canonical NETs and NLS, which together form a fibrous sticky network that entangles C. albicans hyphae and efficiently inhibits their growth.

Inflammation is a multifaceted marker resulting from complex interactions between genetic and lifestyle factors. Emerging evidence suggests Aryl hydrocarbon receptor (AHR) protein may be implicated in the regulation of immune system and inflammatory responses. To investigate whether rs4410790 genotype (TT, TC, CC) near AHR gene is related to serum IgG levels, a marker of chronic inflammation, and whether lifestyle factors modifies the relationship, we conducted a cross-sectional study by recruiting 168 Korean adults. Participants responded to a lifestyle questionnaire and provided oral epithelial cells and blood samples for biomarker assessment. Among these participants, C allele was the minor allele, with the minor allele frequency of 40%. The rs4410790 TT genotype was significantly associated with elevated IgG levels compared with TC/CC genotypes, after adjusting for potential confounders (p = 0.04). The relationship varied significantly by levels of alcohol consumption (P interaction = 0.046) and overweight/obese status (P interaction = 0.02), but not by smoking status (P interaction = 0.64) and coffee consumption (P interaction = 0.55). Specifically, higher IgG levels associated with the TT genotype were evident in frequent drinkers and individuals with BMI≥23kg/m2, but not in their counterparts. Thus, rs4410790 genotype may be associated with IgG levels and the genetic predisposition to higher IgG levels may be mitigated by healthy lifestyle factors like infrequent drinking and healthy weight.

Obesity is a disease commonly associated with urbanization and can also be characterized as a systemic, chronic metabolic condition resulting from an imbalance between energy intake and expenditure. The World Health Organization (WHO) has identified obesity as the most serious chronic disease that is increasingly prevalent in the world population. If left untreated, it can lead to dangerous health issues such as hypertension, hyperglycemia, hyperlipidemia, hyperuricemia, nonalcoholic steatohepatitis, atherosclerosis, and vulnerability to cardiovascular and cerebrovascular events. The specific mechanisms by which obesity affects the development of these diseases can be refined to the effect on immune cells. Existing studies have shown that the development of obesity and its associated diseases is closely related to the balance or lack thereof in the number and function of various immune cells, of which neutrophils are the most abundant immune cells in humans, infiltrating and accumulating in the adipose tissues of obese individuals, whereas NETosis, as a newly discovered type of neutrophil-related cell death, its role in the development of obesity and related diseases is increasingly emphasized. The article reviews the significant role that NETosis plays in the development of obesity and related diseases, such as diabetes and its complications. It discusses the epidemiology and negative impacts of obesity, explains the mechanisms of NETosis, and examines its potential as a targeted drug to treat obesity and associated ailments.

Polymorphonuclear neutrophils (PMN) represent one of the first lines of defence against invading pathogens and are the most abundant leucocytes in the circulation. Generally described as pro-inflammatory cells, recent data suggest that PMN also have immunomodulatory capacities. In response to certain stimuli, activated PMN expel neutrophil extracellular traps (NET), structures made of DNA and associated proteins. Although originally described as an innate immune mechanism fighting bacterial infection, NET formation (or probably rather an excess of NET together with impaired clearance of NET) may be deleterious. Indeed, NET have been implicated in the development of several inflammatory and autoimmune diseases as rheumatoid arthritis or systemic lupus erythematosus, as well as fibrosis or cancer. They have been suggested as a source of (neo)autoantigens or regulatory proteins like proteases or to act as a physical barrier. Different mechanisms of NET formation have been described, leading to PMN death or not, depending on the stimulus. Interestingly, NET may be both pro-inflammatory and anti-inflammatory and this probably partly depends on the mechanism, and thus the stimuli, triggering NET formation. Within this review, we will describe the pro-inflammatory and anti-inflammatory activities of NET and especially how NET may modulate immune responses.

Previous empirical literature has examined the associations between childhood sexual abuse (CSA) exposure, posttraumatic stress disorder (PTSD), and smoking. However, few studies examined symptom-level associations between smoking and PTSD among CSA victims. Thus, the aims of this study were 1) to explore symptom-level associations between smoking and PTSD among combustible cigarette (CC) and electronic cigarette (EC) users exposed to CSA and 2) to compare the differences manifested in two network structures between EC and CC users with CSA experiences.

This cross-sectional study covers all 63 universities and colleges in Jilin province, China, from October 26 to November 18, 2021. A total of 117 769 students participated in this study, while 3479 young adults were exposed to CSA (3.62%, 95% CI = 3.50%-3.73%). Childhood sexual abuse, PTSD, and smoking symptoms were measured using the Childhood Trauma Questionnaire-Short Form (CTQ-SF), 10-item Trauma Screening Questionnaire (TSQ-10), and the 6-item Fagerstrom Test for Nicotine Dependence (FTND-6), respectively. In addition, network analysis was applied to analyse psychopathological symptoms between EC and CC users with CSA experiences. Both the edges and centralities were computed, and the network properties were compared among the two groups.

Four symptoms of PTSD (i.e. emotional cue reactivity, hypervigilance, nightmares, and difficulty concentrating) were both central and bridge symptoms between PTSD and smoking among EC and CC users with CSA experiences. Moreover, compared with CC users with CSA, there were significantly stronger associations between "nightmares" - "difficulty with restrictions" and "irritability / anger" - "more during wake up" among young EC users with CSA.

The four symptoms (i.e. emotional cue reactivity, hypervigilance, nightmares, and difficulty concentrating) were keystones for treatments or interventions targeting these CSA victims with PTSD and smoking symptoms. Increasing efforts should be taken to restrict morning smoking among EC users with CSA. In addition, target interventions and strategies founded on these core symptoms and associations should be implemented to relieve the comorbid PTSD and smoking in EC and CC users with CSA experiences.

Acute exposure to e-cigarette aerosol has been shown to have potentially deleterious effects on the cardiovascular system. However, the cardiovascular effects of habitual e-cigarette use have not been fully elucidated. Therefore, we aimed to assess the association of habitual e-cigarette use with endothelial dysfunction and inflammation - subclinical markers known to be associated with increased cardiovascular risk.

In this cross-sectional study, we analyzed data from 46 participants (23 exclusive e-cigarette users; 23 non-users) enrolled in the VAPORS-Endothelial function study. E-cigarette users had used e-cigarettes for ≥6 consecutive months. Non-users had used e-cigarettes <5 times and had a negative urine cotinine test (<30 ng/mL). Flow-mediated dilation (FMD) and reactive hyperemia index (RHI) were used to assess endothelial dysfunction, and we assayed high-sensitivity C-reactive protein, interleukin-6, fibrinogen, p-selectin, and myeloperoxidase as serum measures of inflammation. We used multivariable linear regression to assess the association of e-cigarette use with the markers of endothelial dysfunction and inflammation.

Of the 46 participants with mean age of 24.3 ± 4.0 years, the majority were males (78%), non-Hispanic (89%), and White (59%). Among non-users, 6 had cotinine levels <10 ng/mL while 17 had levels 10-30 ng/mL. Conversely, among e-cigarette users, the majority (14 of 23) had cotinine ≥500 ng/mL. At baseline, the systolic blood pressure was higher among e-cigarette users than non-users (p=0.011). The mean FMD was slightly lower among e-cigarette users (6.32%) compared to non-users (6.53%). However, in the adjusted analysis, current e-cigarette users did not differ significantly from non-users in their mean FMD (Coefficient=2.05; 95% CI: -2.52-6.63) or RHI (Coefficient= -0.20; 95% CI: -0.88-0.49). Similarly, the levels of inflammatory markers were generally low and did not differ between e-cigarette users and non-users.

Our findings suggest that e-cigarette use may not be significantly associated with endothelial dysfunction and systemic inflammation in relatively young and healthy individuals. Longer term studies with larger sample sizes are needed to validate these findings.

The effects of nicotine and cigarette smoke in many diseases, notably COVID-19 infection, are being debated more frequently. The current basic data for COVID-19 is increasing and indicating the higher risk of COVID-19 infections in smokers due to the overexpression of corresponding host receptors to viral entry. However, current multi-national epidemiological reports indicate a lower incidence of COVID-19 disease in smokers. Current data indicates that smokers are more susceptible to some diseases and more protective of some other. Interestingly, nicotine is also reported to play a dual role, being both inflammatory and anti-inflammatory. In the present study, we tried to investigate the effect of pure nicotine on various cells involved in COVID-19 infection. We followed an organ-based systematic approach to decipher the effect of nicotine in damaged organs corresponding to COVID-19 pathogenesis (12 related diseases). Considering that the effects of nicotine and cigarette smoke are different from each other, it is necessary to be careful in generalizing the effects of nicotine and cigarette to each other in the conducted researches. The generalization and the undifferentiation of nicotine from smoke is a significant bias. Moreover, different doses of nicotine stimulate different effects (dose-dependent response). In addition to further assessing the role of nicotine in COVID-19 infection and any other cases, a clever assessment of underlying diseases should also be considered to achieve a guideline for health providers and a personalized approach to treatment.

NETosis is a critical innate immune mechanism of neutrophils that contributes to the accelerated progression of autoimmune diseases, thrombosis, cancer, and coronavirus disease 2019 (COVID-19). This study qualitatively and quantitatively analyzed the relevant literature by bibliometric methods in order to provide a more comprehensive and objective view of the knowledge dynamics in the field.

The literature on NETosis was downloaded from the Web of Science Core Collection, analyzed with VOSviewer, CiteSpace, and Microsoft for co-authorship, co-occurrence, and co-citation analysis.

In the field of NETosis, the United States was the most influential countries. Harvard University was the most active institutions. Mariana J. Kaplan and Brinkmann V were, respectively, the most prolific and most co-cited authors. Frontiers in Immunology, Journal of Immunology, Plos One, Blood, Science, Journal of Cell Biology, and Nature Medicine were the most influential journals. The top 15 keywords are associated with immunological and NETosis formation mechanisms. The keywords with the strongest burst detection were mainly related to COVID-19 (coronavirus, ACE2, SARS coronavirus, cytokine storm, pneumonia, neutrophil to lymphocyte ratio), and cancer (circulating tumor cell).

Research on NETosis is currently booming. The mechanism of NETosis and its role in innate immunity, autoimmune diseases, especially systemic lupus erythematosus and rheumatoid arthritis, and thrombosis are the focus of research in the field of NETosis. A future study will concentrate on the function of NETosis in COVID-19 and recurrent metastasis of cancer.

d-lactate is a metabolite originating from bacterial metabolism that accumulates as a result of dietary disturbances in cattle, leading to ruminal acidosis. d-lactate exerts functions as a metabolic signal inducing metabolic reprogramming and extracellular trap (ET) release in polymorphonuclear leucocytes (PMNs). We previously demonstrated that d-lactate induces metabolic reprogramming via hypoxia-induced factor 1 alpha (HIF-1α) stabilization in bovine fibroblast-like synoviocytes (FLSs). In the present study, the role of HIF-1 in ET formation induced by d-lactate was assessed. HIF-1α stabilization in PMNs was controlled by mitochondrial reactive oxygen species (_mtROS) release. Furthermore, inhibition of mitochondrial complex I and scavenging of _mtROS decreased d-lactate-triggered ETosis. d-lactate-enhanced HIF-1α accumulation was dependent on the PI3K/Akt pathway but independent of GSK-3β activity. Pharmacological blockade of the PI3K/Akt/HIF-1 and GSK-3β axes inhibited d-lactate-triggered ETosis and downregulated PDK1 and LDHA expression. However, only GSK-3β inhibition decreased the expression of glycogen metabolism enzymes and prevented the decline in glycogen stores induced by d-lactate exposure. The results of this study suggest that _mtROS, PI3K/Akt/HIF-1 and GSK-3β axes regulate carbohydrate metabolism adaptations that support d-lactate-induced ET formation in cattle.

Deltamethrin (DLM), a broad-spectrum pesticide, has been proven to have toxic effects on aquatic organisms. Here, we detected the formation of extracellular traps (ETosis) formation in Manila clam (Ruditapes philippinarum) hemocytes stimulated by three concentrations of DLM (0.01, 0.1 and 1 μg/mL) in vitro, and explored the underlying mechanisms induced by this pesticide. Extracellular DNA structure observation and quantitative results indicated that DLM exposure could obviously induce hemocytes ETosis, especially under high concentration of DLM induction. Moreover, DLM increased the levels of myeloperoxidase (MPO) and reactive oxygen species (ROS) in a dose-dependent manner, and enhanced the mRNA expression of several ROS-related genes. DPI (NADPH oxidase inhibitor) and ABAH (MPO inhibitor) could substantially inhibit DLM-induced extracellular traps (ETs), suggesting that the induced ETs release was caused by the induction of the ROS burst and MPO production. In addition, three concentrations of DLM-induced ETs were also accompanied by mitochondrial dysfunction, such as increasing the production of mitochondrial ROS, leading to a decrease in mitochondrial membrane potential (MMP) and activation of mitochondrial permeability transition pore (MPTP). Taken together, these results will shed new light on the immunotoxicity of DLM in clams and perhaps lays the foundation for health assessment in bivalves.

Neutrophil extracellular traps (NETs) serve to immobilize and kill pathogens, but also can contribute to the progression of several inflammatory and auto-immune diseases, as well as cancer. Whence the importance of elucidating the mechanisms underlying NET formation. In this regard, the PI3K signaling pathway has been shown to be crucial; yet little is known about which of its components are involved. Here, we identified the PI3K isoforms and associated signaling partners that are mobilized in response to different classes of physiological NET inducers (inflammatory cytokines, growth factors, chemoattractants). NET generation was assessed by microscopy and signalling molecule activation by immunoblot using phospho-antibodies. Across the various stimuli, PI3Kα and PI3Kγ isoforms clearly contributed to NET induction, while the participation of other isoforms was stimulus-dependent. Some PI3K isoforms were also found to signal through Akt, the canonical downstream effector of PI3K, while others did not. Downstream of PI3K, mTOR and PLCγ2 were used by all stimuli to control NET generation. Conversely, the involvement of other kinases depended on the stimulus - both TNFα and GM-CSF relied on PDK1 and Akt; and both TNFα and fMLP additionally used S6K. We further established that all PI3K isoforms and downstream effectors act belatedly in NET generation, as reported previously for PI3K. Finally, we revisited the PI3K-PDK1-Akt signaling hierarchy in human neutrophils and again found stimulus-dependent differences. Our data uncover unsuspected complexity and redundancy in the signaling machinery controlling NET formation through the all-important PI3K pathway. Conserved signaling molecules represent therapeutic targets for pathologies involving NETs and in this regard, the existence of drugs currently used in the clinic or undergoing clinical trials (which target PI3K isoforms, mTOR or Akt), underscores the translational potential of our findings.

Cigarette smoke (CS) was known for its effect of increasing oxidative stress that could trigger tissue injury and endothelial dysfunction mediated by free radicals and reactive oxygen species (ROS). ROS itself is a key signaling molecule that plays a role in the development of inflammatory disorders. Nuclear factor erythroid2 related factor2 (Nrf2) is the main regulator of antioxidant cellular response to cell and tissue-destroying components caused by CS. Nrf2 protein that is significantly activated in the smokers' small airway epithelium is followed by a series of gene expression changes in the same cells. This study aims to observe differentially expressed genes (DEGs) in the human small airway epithelium of smokers compared to genes whose expression changes due to astaxanthin (AST) treatment, an antioxidant compound that can modulate Nrf2. Gene expression data that was stored in the GEO browser (GSE 11952) was analyzed using GEO2R to search for DEG among smokers and nonsmokers subject. DEG was further compared to those genes whose expression changes due to astaxanthin treatment (AST) that were obtained from the Comparative Toxicogenomics Database (CTD; https://ctdbase.org/). DEG (p < 0.05) analysis result shows that there are 23 genes whose expression regulation is reversed compared to gene expression due to AST treatment. The gene function annotations of the 23 DEGs showed the involvement of some of these genes in chemical and oxidative stress, reactive oxygen species (ROS), and apoptotic signaling pathways. All of the genes were involved/associated with chronic bronchitis, adenocarcinoma of the lung, non-small-cell lung carcinoma, carcinoma, small cell lung carcinoma, type 2 diabetes mellitus, emphysema, ischemic stroke, lung diseases, and inflammation. Thus, AST treatment for smokers could potentially decrease the development of ROS and oxidative stress that leads to inflammation and health risks associated with smoking.

Chronic obstructive pulmonary disease (COPD) is an important public health challenge worldwide, and is usually caused by significant exposure to noxious agents, particularly cigarette smoke. Recent studies have revealed that excessive production of neutrophil extracellular traps (NETs) in the airways is associated with disease severity in COPD patients. NETs are extracellular neutrophil-derived structures composed of chromatin fibers decorated with histones and granule proteases including neutrophil elastase (NE). However, the effective prevention of NET formation in COPD remains elusive. Here, we demonstrated that treatment with GW311616A, a potent and selective inhibitor of NE, prevented cigarette smoke extract (CSE)-induced NET formation in human neutrophils by blocking NE nuclear translocation and subsequent chromatin decondensation. Inhibition of NE also abrogated CSE-induced ROS production and migration impairment of neutrophils. Administration of GW311616A in vivo substantially reduced pulmonary generation of NETs while attenuating the key pathological changes in COPD, including airway leukocyte infiltration, mucus-secreting goblet cell hyperplasia, and emphysema-like alveolar destruction in a mouse model of COPD induced by chronic cigarette smoke exposure. Mice treated with GW311616A also showed significant attenuation of neutrophil numbers and percentages and the levels of neutrophil chemotactic factors (LTB4, KC, and CXCL5) and proinflammatory cytokines (IL-1β, and TNF-α) in bronchoalveolar lavage fluid compared to mice treated with cigarette smoke exposure only. Furthermore, GW311616A treatment considerably improved lung function in the COPD mouse model, including preventing the decline of FEV₁₀₀/FVC and delta PEF as well as inhibiting the increase in FRC, TLC, and FRC/TLC. Overall, our study suggests that NE plays a critical role in cigarette smoke-induced NET formation by neutrophils and that inhibition of NE is a promising strategy to suppress NET-mediated pathophysiological changes in COPD.

Smoking undoubtedly affects human health. Investigating 2318 representative patients at a level 1 trauma center identified delayed wound healing, tissue infections, and/or sepsis as main complications in smokers following trauma and orthopedic surgery. Therefore, smoking cessation is strongly advised to improve the clinical outcome in these patients, although smoking cessation often fails despite nicotine replacement therapy raising the need for specific interventions that may reduce the complication rate. However, the underlying mechanisms are still unknown. In diabetics, delayed wound healing and infections/sepsis are associated with increased neutrophilic PADI4 expression and formation of neutrophil extracellular traps (NETs). The aim was to investigate if similar mechanisms hold for smokers. Indeed, our results show higher PADI4 expression in active and heavy smokers than non-smokers, which is associated with an increased complication rate. However, in vitro stimulation of neutrophils with cigarette smoke extract (CSE) only moderately induced NET formation despite accumulation of reactive oxygen species (ROS). Physiological levels of nicotine and its main metabolite cotinine more effectively induced NET formation, although they did not actively induce the formation of ROS, but interfered with the activity of enzymes involved in anti-oxidative defense and NET formation. In summary, we propose increased formation of NETs as possible triggers for delayed wound healing, tissue infections, and/or sepsis in smokers after a major trauma and orthopedic surgery. Smoking cessation might reduce this effect. However, our data show that smoking cessation supported by nicotine replacement therapy should be carefully considered as nicotine and its metabolite cotinine effectively induced NET formation in vitro, even without active formation of ROS.

Cell-free DNA (cfDNA) is elevated in several disease states. Metabolic syndrome is a constellation of factors associated with poor cardiometabolic outcomes. This study examined associations of cfDNA from the nucleus (cf-nDNA) and mitochondria (cf-mtDNA), C-reactive protein (CRP), and metabolic syndrome risk, in low-active smokers with depressive symptoms.

Participants (N = 109; mean age 47) self-reported medical history. Physical activity was determined by accelerometry and anthropometrics were measured. Blood was collected and analyzed for cf-nDNA, cf-mtDNA, CRP, triglycerides, high-density lipoprotein, hemoglobin A1c. A continuous metabolic syndrome composite risk score was calculated. Relationships of cf-nDNA, cf-mtDNA, CRP, and cardiometabolic risk were examined with correlations and linear regression.

CRP and cf-nDNA were significantly associated with metabolic syndrome risk (r = .39 and r = .31, respectively), cf-mtDNA was not (r = .01). In a linear regression, CRP and cf-nDNA significantly predicted the metabolic syndrome risk score, findings that remained significant controlling for age, gender, nicotine dependence, and physical activity.

Associations of cf-nDNA with both CRP and metabolic risk suggest a role for cf-nDNA in inflammatory processes associated with metabolic syndrome. The negative findings for cf-mtDNA suggest distinct roles for cf-nDNA and cf-mtDNA in these processes.

Although emerging evidence reveals that vaping alters the function of the central nervous system, the effects of maternal vaping on offspring brain development remain elusive. Using a well-established in utero exposure model, we performed single-nucleus ATAC-seq (snATAC-seq) and RNA sequencing (snRNA-seq) on prenatally e-cigarette-exposed rat brains. We found that maternal vaping distorted neuronal lineage differentiation in the neonatal brain by promoting excitatory neurons and inhibiting lateral ganglionic eminence-derived inhibitory neuronal differentiation. Moreover, maternal vaping disrupted calcium homeostasis, induced microglia cell death, and elevated susceptibility to cerebral ischemic injury in the developing brain of offspring. Our results suggest that the aberrant calcium signaling, diminished microglial population, and impaired microglia-neuron interaction may all contribute to the underlying mechanisms by which prenatal e-cigarette exposure impairs neonatal rat brain development. Our findings raise the concern that maternal vaping may cause adverse long-term brain damage to the offspring.

Neutrophils are the most abundant leukocyte in human blood. They are critical for fighting infections and are involved in inflammatory diseases. Mitochondria are indispensable for eukaryotic cells, as they control the biochemical processes of respiration and energy production. Mitochondria in neutrophils have been underestimated since glycolysis is a major metabolic pathway for fuel production in neutrophils. However, several studies have shown that mitochondria are greatly involved in multiple neutrophil functions as well as neutrophil-related diseases. In this review, we focus on how mitochondrial components, metabolism, and related genes regulate neutrophil functions and relevant diseases.