Search Results (477)

Cancer remains a major global health challenge requiring the development of diagnostic and therapeutic strategies. Liquid biopsy is considered a promising minimally invasive tool for cancer screening, prognosis and treatment monitoring. Recent studies suggest that neutrophil extracellular traps (NETs) may also be potential liquid biopsy markers. NETs are web-like chromatin structures released by neutrophils in response to various stimuli to trap and neutralize pathogens. However, excessive or dysregulated NET formation has been implicated in tumor progression and metastasis. Elevated levels of NETs have been observed in patients with various types of cancer and correlate with disease stage and prognosis. The presence of NET markers such as citrullinated histone H3 (H3Cit), neutrophil elastase (NE) and myeloperoxidase (MPO) has been associated with higher tumor burden and poorer clinical outcomes. Several studies have shown a positive correlation between NET markers and circulating free DNA (cfDNA) levels, suggesting that NETs may increase the sensitivity of liquid biopsy in detecting and monitoring cancer progression. This review examines the role of NETs in the tumor microenvironment, their contribution to cancer progression and metastasis, and their potential use in liquid biopsy and cancer therapy. Full article

Sepsis is a clinical syndrome characterized by a dysregulated host response to infection, frequently resulting in septic shock and multi-organ failure. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in the pathophysiology of sepsis. NETs are extracellular structures composed of chromatin DNA, histones, and granular proteins released by neutrophils through a specialized form of cell death known as NETosis. While NETs contribute to the containment of pathogens, their excessive or dysregulated production in sepsis is associated with endothelial damage, immunothrombosis, and organ dysfunction. Several NET-associated biomarkers have been identified, including circulating cell-free DNA (cfDNA), histones, MPO-DNA complexes, and neutrophil elastase–DNA complexes, which correlate with the disease severity and prognosis. Therapeutic strategies targeting NETs are currently under investigation. Inhibition of NET formation using PAD4 inhibitors or ROS scavengers has shown protective effects in preclinical models. Conversely, DNase I therapy facilitates the degradation of extracellular DNA, reducing the NET-related cytotoxicity and thrombotic potential. Additionally, heparin and its derivatives have demonstrated the ability to neutralize NET-associated histones and mitigate coagulopathy. Novel approaches include targeting upstream signaling pathways, such as TLR9 and IL-8/CXCR2, offering further therapeutic promise. Full article

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a heterogeneous group of small-vessel vasculitides, characterized by the presence of antibodies binding to myeloperoxidase (MPO) and proteinase-3 (PR3) found in neutrophil granules. Apart from being the target of ANCA, neutrophils actively contribute to the vicious cycle of inflammation and vascular damage in AAV. On the other hand, platelets have recently been recognized as essential for thrombosis and as inflammatory effectors that collaborate with neutrophils, reinforcing the generation of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs) in those diseases. Neutrophils exhibit morphological and functional heterogeneity in AAV, reflecting the complexity of their contribution to disease pathogenesis. Since long-term immunosuppression may be related to serious infections and malignancies, there is an urgent need for reliable biomarkers of disease activity to optimize the management of AAV. This review summarizes the current understanding of the role of neutrophils and platelets in the pathogenesis of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), focusing on their crosstalk, and highlights the potential for identifying novel biomarkers relevant for predicting the disease course and its relapses. Full article

Acute respiratory distress syndrome (ARDS) is an inflammatory pulmonary condition that remains at alarming rates of fatality, with neutrophils playing a vital role in its pathogenesis. Beyond their classical antimicrobial functions, neutrophils contribute to pulmonary injury via the release of reactive oxygen species, proteolytic enzymes, and neutrophil extracellular traps (NETs). To identify targets for treatment, it was found that epigenetic mechanisms, including histone modifications, hypomethylation, hypermethylation, and non-coding RNAs, regulate neutrophil phenotypic plasticity, survival, and inflammatory potential. It has been identified that neutrophils in ARDS patients exhibit abnormal methylation patterns and are associated with altered gene expression and prolonged neutrophil activation, thereby contributing to sustained inflammation. Histone citrullination, particularly via PAD4, facilitates NETosis, while histone acetylation status modulates chromatin accessibility and inflammatory gene expression. MicroRNAs have also been shown to regulate neutrophil activity, with miR-223 and miR-146a potentially being biomarkers and therapeutic targets. Neutrophil heterogeneity, as evidenced by distinct subsets such as low-density neutrophils (LDNs), varies across ARDS etiologies, including COVID-19. Single-cell RNA sequencing analyses, including the use of trajectory analysis, have revealed transcriptionally distinct neutrophil clusters with differential activation states. These studies support the use of epigenetic inhibitors, including PAD4, HDAC, and DNMT modulators, in therapeutic intervention. While the field has been enlightened with new findings, challenges in translational application remain an issue due to species differences, lack of stratification tools, and heterogeneity in ARDS presentation. This review describes how targeting neutrophil epigenetic regulators could help regulate hyperinflammation, making epigenetic modulation a promising area for precision therapeutics in ARDS. Full article

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), results from dysregulated immune responses that drive chronic intestinal inflammation. Neutrophils, as key effectors of the innate immune system, contribute to IBD through multiple mechanisms, including the release of reactive oxygen species (ROS), pro-inflammatory cytokines, and neutrophil extracellular traps (NETs). NETs are web-like structures composed of DNA, histones, and associated proteins including proteolytic enzymes and antimicrobial peptides. NET formation is increased in IBD and has a context-dependent role; under controlled conditions, NETs support antimicrobial defense and tissue repair, whereas excessive or dysregulated NETosis contributes to epithelial injury, barrier disruption, microbial imbalance, and thrombotic risk. This review examines the roles of neutrophils and NETs in IBD. We summarize recent single-cell and spatial-omics studies that reveal extensive neutrophil heterogeneity in the inflamed gut. We then address the dual role of neutrophils in promoting tissue damage—through cytokine release, immune cell recruitment, ROS production, and NET formation—and in supporting microbial clearance and mucosal healing. We also analyze the molecular mechanisms regulating NETosis, as well as the pathways involved in NET degradation and clearance. Focus is given to the ways in which NETs disrupt the epithelial barrier, remodel the extracellular matrix, contribute to thrombosis, and influence the gut microbiota. Finally, we discuss emerging therapeutic strategies aimed at restoring NET homeostasis—such as PAD4 inhibitors, NADPH oxidase and ROS pathway modulators, and DNase I—while emphasizing the need to preserve antimicrobial host defenses. Understanding neutrophil heterogeneity and NET-related functions may facilitate the development of new therapies and biomarkers for IBD, requiring improved detection tools and integrated multi-omics and clinical data. Full article

Metastases are the leading cause of cancer-related deaths. The spread of neoplasms involves multiple mechanisms, with metastatic tumors exhibiting molecular behaviors distinct from their primary counterparts. The key hallmarks of metastatic lesions include chromosomal instability, copy number alterations (CNAs), and a reduced degree of subclonality. Furthermore, metabolic adaptations such as enhanced glycogen synthesis and storage, as well as increased fatty acid oxidation (FAO), play a critical role in sustaining energy supply in metastases and contributing to chemoresistance. FAO promotes the infiltration of macrophages into the tumor, where they polarize to the M2 phenotype, which is associated with immune suppression and tissue remodeling. Additionally, the tumor microbiome and the action of cytotoxic drugs trigger neutrophil extravasation through inflammatory pathways. Chemoresistant neutrophils in the tumor microenvironment can suppress effector lymphocyte activation and facilitate the formation of neutrophil extracellular traps (NETs), which are linked to drug resistance. This article examines the genomic features of metastatic tumors, along with the metabolic and immunological dynamics within the metastatic tumor microenvironment, and their contribution to drug resistance. It also discusses the molecular mechanisms underlying resistance to chemotherapeutic agents commonly used in the treatment of metastatic cancer. Full article

Pulmonary embolism (PE) is an under-recognised yet serious complication in patients with acute ischaemic stroke (AIS), contributing significantly to morbidity and mortality. The interplay of traditional risk factors—such as immobility, endothelial dysfunction, and hypercoagulability—with AIS-specific conditions, including atrial fibrillation, malignancy, and reperfusion therapies, complicates both diagnosis and management. Despite available prophylactic strategies, including low-molecular-weight heparin and intermittent pneumatic compression, their use remains limited by bleeding concerns and a lack of tailored guidelines. This review synthesises the current evidence on the incidence, risk factors, pathophysiology, diagnostic approaches, and preventive strategies for PE in AIS, identifying critical gaps in risk stratification and clinical decision-making. We propose a novel mechanistic framework—the Brain–Lung Thromboinflammatory Axis Hypothesis—which posits that stroke-induced systemic inflammation, neutrophil extracellular trap (NET) formation, and pulmonary endothelial activation may drive in situ pulmonary thrombosis independent of deep vein thrombosis. This conceptual model highlights new diagnostic and therapeutic targets and underscores the need for stroke-specific VTE risk calculators, biomarker-guided prophylaxis, and prospective trials to optimise prevention and outcomes in this vulnerable population. Full article

Venous thromboembolism (VTE) represents a significant complication of cancer immunotherapy, with emerging evidence suggesting distinct pathophysiological mechanisms compared to traditional chemotherapy-associated thrombosis. This narrative review examines the epidemiology and pathogenesis of VTE in patients receiving immunotherapies for cancer including immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapy, bispecific T-cell engagers (BiTEs), among others. Real-world studies demonstrate a wide range of VTE incidence rates in ICI recipients, with potential mechanisms including exacerbated underlying interleukin-8-mediated inflammatory pathways and consequent neutrophil extracellular trap (NET) formation. CAR T-cell therapy is associated with unique hemostatic challenges, including concurrent thrombotic and bleeding risks related to cytokine release syndrome. Current risk assessment tools show limited predictive utility in patients receiving immunotherapies for cancer, highlighting the need for novel stratification models. Future research priorities include developing immunotherapy-specific risk prediction tools, elucidating mechanistic pathways linking immune activation to thrombosis, and establishing evidence-based and tailored thromboprophylaxis strategies. As cancer immunotherapy continues to evolve, understanding and mitigating thrombotic complications remains crucial for optimizing patient outcomes. Full article

Objectives: High-calorie diets are linked to increased risks of chronic inflammation and immune dysfunction, yet their role in modulating pneumonia severity remains unclear. Focusing on the interactions among gut-originating short-chain fatty acids (SCFAs), neutrophil function, and histone deacetylases (HDACs), this research examined the exacerbating effects of a high-calorie diet on pneumonia in rats. Methods: Male Sprague-Dawley rats (3 weeks old, 110 ± 10 g) were allocated among four groups: normal diet (N), high-calorie diet (G), LPS-induced pneumonia (P), and high-calorie diet combined with lipopolysaccharide (LPS)-induced pneumonia (GP). LPS was administered via aerosolization for three days. Fecal, serum, and lung SCFA levels were quantified via GC-MS. Neutrophil extracellular traps (NETs) formation, neutrophil apoptosis, and HDAC activity were assessed using immunofluorescence, TUNEL assays, and qRT-PCR. Propionate supplementation and HDAC inhibitor (trichostatin A) interventions were applied to validate mechanistic pathways. Results: The group GP exhibited exacerbated lung inflammation, increased NETs release, and reduced neutrophil apoptosis compared to the group P. Propionate levels in feces, serum, and lung tissues decreased sharply in GP rats, correlating with elevated HDAC1/2/3/6 activity and reduced histone acetylation. Propionate supplementation or HDAC inhibition significantly attenuated lung injury, suppressed NETs, and restored neutrophil apoptosis. Conclusions: High-calorie diets exacerbate pneumonia by depleting gut-derived propionate, which drives HDAC-mediated NETs overproduction and impairs neutrophil apoptosis. Restoring propionate levels or targeting HDACs may offer therapeutic strategies for diet-aggravated respiratory diseases. Mechanistically, propionate-mediated HDAC inhibition demonstrates proof-of-concept efficacy in modulating H4 acetylation, warranting further investigation in disease-specific pneumonia models. Full article

This review highlights recent insights into the pathophysiology and therapeutic strategies for improving biocompatibility in hemodialysis. Hemodialysis activates the innate immune system, particularly the complement cascade and neutrophils, leading to acute microinflammation. Interleukin-8 (IL-8), which increases during dialysis, promotes neutrophil chemotaxis and neutrophil extracellular trap (NET) formation, triggering myeloperoxidase (MPO) release and oxidative stress. Neutrophil accumulation in atherosclerotic plaques exacerbates vascular inflammation through IL-6 upregulation. Elevated levels of IL-8, MPO, and NET-related biomarkers are associated with increased all-cause and cardiovascular mortality in dialysis patients. Strategies to mitigate these effects include the use of advanced membrane materials (e.g., AN69, vitamin E-coated, polymethyl methacrylate), novel dialysis modalities (e.g., high-volume online hemodiafiltration, cool dialysate, hydrogen-enriched dialysate), and citrate-based anticoagulation. These approaches aim to suppress complement activation, reduce oxidative stress, and limit neutrophil-induced damage. Enhancing biocompatibility is crucial for reducing cardiovascular complications and improving outcomes in dialysis patients. Suppressing the innate immune response during dialysis may become a future cornerstone in extracorporeal blood purification therapy. Full article

Sepsis is a dysregulated host response to an infection characterized by the presence of coagulopathy and endothelial dysfunction. Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils that bind invasive pathogens. These extracellular traps are involved in the activation and dysfunction of several pathways during the process of sepsis syndrome, including the immune response to injury, inflammation, and coagulation. Those formations consist of many molecules that have been studied as biomarkers for multiple sepsis pathophysiological pathways that reflect various complications. The best-studied segments of such formations, circulating free DNA, citrullinated histone 3 and myeloperoxidase, are considered to contribute to upscaling specificity. Plenty of NET end-products have been recently studied as indirect biomarkers for NET-related sepsis complications. Several studies have examined the relationship between NET end-products and established sepsis severity scores, such as Acute Physiology and Chronic Health Evaluation II (APACHE 2) and Multiple Organ Dysfunction Score (MODS). These studies also explore how these end-products contribute to the prognosis of acute respiratory distress syndrome (ARDS), mortality, and their efficacy in evaluating disseminating intravascular coagulation (DIC). This is a short review of the current literature regarding the evaluation of neutrophil extracellular trap levels in the prognosis of sepsis patients. Full article

In swine reproduction, immune-mediated mechanisms such as neutrophil extracellular trap (NET) formation can affect sperm function and reduce fertility outcomes. This study evaluated the capacity of antioxidant and reproductive compounds—butylated hydroxytoluene (BHT), prostaglandin E₂ (PGE₂), bovine serum albumin (BSA), and seminal plasma (SP)—to modulate NETosis in co-cultures of swine neutrophils and cryopreserved spermatozoa. NET formation was quantified by nuclear area expansion and validated by digital cytometry and immunofluorescence. BHT (0.5 mM) and PGE₂ (10 µM) produced the most significant inhibitory effects, reducing NETotic cell percentages from 34.5 ± 2.7% (sperm-exposed controls) to 12.2 ± 1.3% and 14.5 ± 2.1%, respectively (p < 0.01). SP at 20% decreased NETosis to 16.8 ± 1.8%, while BSA (0.5%) achieved a moderate reduction to 21.3 ± 2.5%. Flow cytometry revealed reduced peroxynitrite levels in sperm treated with SP and BSA. Two NET phenotypes (aggNETs and sprNETs) were identified. BTS medium enhanced NET formation, whereas DNase I degraded NETs effectively. These findings identify porcine NETosis as a redox-sensitive pathway modulated in vitro, suggesting an immunological role in enhancing sperm preservation for swine artificial insemination. Full article

Neutrophils are essential components of innate immunity, executing a range of effector functions including phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETs). A key hallmark of NET formation is the presence of citrullinated histone H3 (CitH3), produced by peptidylarginine deiminases (PAD2 and PAD4) to facilitate chromatin decondensation. While NETs play critical antimicrobial roles, excessive or dysregulated NET formation, termed NETosis, can drive tissue injury, chronic inflammation, and organ dysfunction across a wide spectrum of diseases. Beyond its structural role within NETs, CitH3 acts as a damage-associated molecular pattern (DAMP), amplifying immune activation and pathological inflammation. Elevated CitH3 levels have been identified as biomarkers in sepsis, viral infections, ischemia–reperfusion injury, organ transplantation, diabetic wounds, autoimmune diseases, and cancer. Despite increasing recognition of CitH3’s pathogenic contributions, its therapeutic potential remains largely untapped. This review summarizes recent advances in understanding the role of CitH3 in NETosis and immune dysfunction, highlights emerging strategies targeting CitH3 therapeutically, and identifies critical knowledge gaps. Collectively, these insights position CitH3 as a promising druggable biomarker for the diagnosis, prognosis, and treatment of acute and chronic inflammatory diseases. Full article

The fibrin matrix of thrombi is intertwined with neutrophil extracellular traps (NETs) containing histones that render resistance to fibrinolysis. During NET formation, histones are citrullinated. Our study addresses the question of whether citrullination modifies the fibrin-stabilizing effects of histones. We studied the structure and viscoelastic properties of fibrin formed in the presence of native or citrullinated H1 and core histones by scanning electron microscopy, clot permeation, and oscillation rheometry. The kinetics of fibrin formation and its dissolution were followed by turbidimetry and thromboelastometry. Co-polymerizing H1 with fibrin enhanced the mechanical strength of the clots, thickened the fibrin fibers, and enlarged the gel pores. In contrast, the addition of core histones resulted in a reduction in the fiber diameter, and the pores were only slightly larger, whereas the mechanical stability was not modified. Plasmin-mediated fibrinogen degradation was delayed by native and citrullinated core histones, but not by H1, and the action of des-kringle1-4-plasmin was not affected. Plasmin-mediated fibrinolysis was inhibited by native and citrullinated core histones, and this effect was moderated when the kringle domains of plasmin were blocked or deleted. These findings suggest that in NET-containing thrombi that are rich in core histones, alternative fibrinolytic enzymes lacking kringle domains are more efficient lytic agents than the classic plasmin-dependent fibrinolysis. Full article