Search Results (233)

Neutrophils, a first-line defender, has a multifaceted presence in chronic inflammation, autoimmune pathology, and tumor progression. The microenvironmental cues facilitate functional plasticity and phenotypic heterogeneity to neutrophils that enable both their protective and pathogenic roles. Autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA) display the presence of dysregulated subsets of neutrophil, such as low-density granulocytes (LDGs) that promote proinflammation and contribute to tissue damage via NETosis and type I interferon-mediated signaling. In cancer, particularly tumors, they exhibit tumor-associated neutrophils (TANs) which may polarize either towards anti-tumorigenic ‘N1’ or pro-tumorigenic ‘N2’ phenotypes based on available modulators such as TGF-β and leucine-driven epigenetic modifications. The development in neutrophil biology has introduced several novel therapeutic strategies that allow NET targeting, inhibition of chemokine receptors like CXCR2, and exploration of neutrophil-derived biomarkers for diagnosis and disease monitoring. Such findings encourage the importance of neutrophils as both effectors and therapeutic targets in inflammatory and neoplastic conditions. Full article

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus that is associated with long-term morbidity and mortality. Pathomorphological findings of LN are broadly divided into proliferative lupus nephritis (PLN) and membranous lupus nephritis (MLN). PLN is characterized by diffuse global or segmental proliferative glomerulonephritis with significant infiltration of inflammatory cells. Type 1 T-helper (Th1) cells, which predominate under inflammatory conditions, and NETosis, as the process of forming neutrophil extracellular traps (NETs), are key factors in the development of PLN. Meanwhile, MLN is characterized by diffuse membranous nephropathy (MN) with global granular subepithelial immune deposits. MLN patients usually experience massive proteinuria, and occasionally show an unfavorable renal prognosis despite aggressive treatment, similar to PLN patients. Intriguingly, in some instances, MLN patients do not show the general immunoserological characteristics of SLE, such as low serum complement and elevated anti-DNA antibody titers. Several reports have indicated an association between Th2 cell dominance and the development of MLN. Moreover, exostosin 1 (EXT1) and exostosin 2 (EXT2) on the glomerular basement membrane have recently been discovered as novel putative antigens for secondary MN, and have been shown to be up-regulated in patients with MLN. To date, many studies have focused on the dissimilarities between PLN and MLN. However, the reason for two polar morphological forms existing within the same disease is not completely clear. The present review addresses published observations on this topic in addition to providing our assertion regarding characteristic NETosis and glomerular EXT1/EXT2 expressions between PLN and MLN. Full article

Neutrophils are the first line of defense of the human immune system against pathogens. Photobiomodulation, mediated by mitochondrial photoacceptors such as cytochrome c oxidase, has emerged as a method to modulate neutrophil function through targeted light exposure. Despite the extensive characterization of neutrophil extracellular traps (NETs) formation (NETosis), the wavelength-specific modulation of neutrophil photoactivation and the involvement of redox pathways remain poorly defined. In this study, the effects of monochromatic (365 nm, 415 nm, 437 nm, and 625 nm) and dichromatic LED-light irradiation on NETs formation were systematically examined. The highest netotic responses were elicited by UV-A (365 nm) and violet-blue light (415 nm), whereas 437 nm showed the lowest induction and 625 nm stimulated a moderate netotic response. The pharmacological inhibition of NETosis induced by 365 nm and 415 nm irradiation with specific NADPH oxidase inhibitor, apocynin, and mitochondrial reactive oxygen species (mtROS) scavenger, MitoTEMPO, attenuated NETs formation by engaging both enzymatic and mitochondrial oxidative sources. Notably, mtROS played a dominant role under 415 nm stimulation in contrast to 365 nm-induced NETosis as demonstrated by higher sensitivity to MitoTEMPO. Importantly, combined simultaneous irradiation with 415 nm and 625 nm LEDs resulted in a significant suppression of NETs formation by more than 50%, highlighting a potent inhibitory synergy observed for the first time and suggesting a new approach of wavelength pairing to modulate neutrophil activation. These results were further supported by measurements of ROS production using a luminol-amplified chemiluminescence assay. Collectively, these findings delineate a wavelength- and ROS-dependent framework for light-induced neutrophil activation, with mitochondrial pathways exerting central control particularly under short-wavelength irradiation. Full article

Alpha-1 antitrypsin deficiency (AATD) represents a paradigmatic genetic disorder with well-characterized hepatic manifestations but relatively underexplored pulmonary implications. While liver involvement has been extensively reviewed, the underlying mechanisms of lung disease progression remain poorly understood, particularly regarding immunological pathways and inflammatory processes. The pathophysiology involves defective alpha-1 antitrypsin (AAT) production, including AAT variants that induce neutrophil elastase activity, causing progressive alveolar destruction and sustained inflammation, leading to emphysema, as one of the main components of chronic obstructive pulmonary disease (COPD). AATD and smoking represent major risk factors for COPD, the third leading cause of death worldwide at present. In AATD patients, neutrophils, which constitute the majority of circulating leukocytes, become dysregulated. Under normal conditions, cells perform essential functions, including phagocytosis and neutrophil extracellular trap formation (NETosis); in AATD, however, they accumulate excessively in alveolar spaces due to impaired elastase control. The accumulation of Z-AAT polymers within epithelial cells creates a pathological cycle, acting as chemoattractants that sustain pro-inflammatory responses and contribute to chronic obstructive pulmonary disease development. In addition, monocytes, representing a smaller fraction of leukocytes, migrate to inflammatory sites and differentiate into macrophages while secreting AAT with anti-inflammatory properties. However, in PiZZ patients, this protective mechanism fails, as polymer accumulation within cells reduces both AAT secretion and the number of protective human leukocyte antigen(HLA)-DR-monocyte subsets. In particular, macrophages demonstrate remarkable plasticity, switching between pro-inflammatory M1 (classically activated macrophages) and tissue-repairing M2 (alternatively activated macrophages) phenotypes based on environmental cues. In AATD, this adaptive capability becomes compromised due to intracellular polymer accumulation, leading to impaired phagocytic function and dysregulated cytokine production and ultimately perpetuating chronic inflammation and progressive tissue damage. Recent advances in induced pluripotent stem cell (iPSC) technology have facilitated alveolar epithelial cell (AEC) generation, in addition to the correction of AATD mutations through gene editing systems. Despite the limitations of AAT correction, iPSC-derived organoid models harboring AATD mutations can deliver important insights into disease pathophysiology, while gene editing approaches help demonstrate causality between specific mutations and observed phenotypes. Therefore, in this review, we investigated recent studies that can serve as tools for gene editing and drug development based on recently developed iPSC-related technologies to understand the pathogenesis of AATD. Full article

Cardiovascular disease (CVD) is currently recognized as one of the leading health threats to humanity. Neutrophils play an important role in innate immune response. The activation of neutrophils leads to the release of neutrophil extracellular traps (NETs) in response to various stimuli. Appropriate NETs are essential for maintaining homeostasis in the body, while excessive NETs will cause pathological damage. Accumulating evidence indicates that NETs are implicated in CVD pathophysiology. This review aims to provide a comprehensive review of the characteristics, signaling pathways, and interactions of NETs with other immune cells, and the comparisons of NETosis with other cell deaths, focusing on the role of NETs in CVDs. Furthermore, this study provides a theoretical basis for further improvement in targeted NET therapy for CVD. Full article

Gestational complications, such as preeclampsia and gestational diabetes mellitus (GDM), pose significant risks to maternal and fetal health and increase long-term cardiovascular disease risk in offspring. This review aims to synthesize current knowledge on the roles of ferroptosis and neutrophil extracellular trap formation (NETosis)—two regulated cell death pathways—in these pregnancy-related conditions. We performed a comprehensive analysis of preclinical and clinical studies that investigate the involvement of dysregulated iron metabolism, oxidative stress, inflammation, and endothelial dysfunction mediated by ferroptosis and NETosis in gestational pathologies. Evidence indicates that disturbances in maternal iron homeostasis and enhanced formation of lipid peroxides and NETs contribute to placental dysfunction and systemic inflammation, exacerbating disease severity. Therapeutic strategies targeting these pathways are emerging but require further validation. Our review also identifies key gaps in mechanistic understanding, biomarker development, and translational research needs. We conclude that modulation of ferroptosis and NETosis offers promising avenues for improving diagnosis and treatment of pregnancy complications, though carefully designed clinical studies are essential to confirm their clinical utility and safety. Full article

Background: Excessive formation of neutrophil extracellular traps (NETs) leads to NETosis, accompanied by the release of citrullinated histone H3 (CitH3), a key mediator of septic inflammation. However, the role of CitH3 in sterile inflammation, such as acute myocardial infarction (MI) and post-MI heart failure, remains incompletely understood. Methods and Results: We investigated the role of CitH3, a byproduct of NETosis, in myocardial ischemia/reperfusion (I/R) injury using a murine MI model. C57BL/6J mice were subjected to left coronary artery (LCA) occlusion followed by reperfusion and treated with either a humanized anti-CitH3 monoclonal antibody (hCitH3-mAb) or control human IgG. In mice undergoing 40 min of LCA occlusion and 24 h of reperfusion, hCitH3-mAb administered 10 min before reperfusion significantly reduced infarct size by 36% compared to control (p < 0.05). Plasma levels of CitH3, IL-1β, and interferon-β were significantly elevated following MI but were attenuated by hCitH3-mAb. In addition, plasma and cardiac tissue from treated mice showed significantly lower levels of citrate synthase, a marker of mitochondrial injury, suggesting that hCitH3-mAb preserved mitochondrial integrity after MI. In mice undergoing 50 min of LCA occlusion and 21 days of reperfusion, longitudinal echocardiography revealed preservation of left ventricular ejection fraction (LVEF) in hCitH3-mAb-treated mice, with significant improvement observed on days 7, 14, and 21 post-MI (p < 0.05 vs. control). hCitH3-mAb also mitigated myocardial fibrosis and preserved tissue architecture. Conclusions: These findings demonstrated CitH3 as a critical mediator of myocardial injury and adverse remodeling following acute MI. Neutralization of CitH3 via hCitH3-mAb attenuates I/R injury and preserves cardiac function by mitigating inflammation and protecting mitochondrial integrity. Targeting CitH3 represents a promising therapeutic strategy to prevent heart failure following MI. Full article

Tenrecs are heterothermic burrowing mammals, which are capable of withstanding extreme environmental stressors, including during hibernation. Their phylogenetic position as reminiscent of an ancestral placental mammal makes tenrecs a unique model for evolutionarily conserved traits, with potential translatability to human physiology and pathobiology, including adaptations to extreme environments. In this study, we compared tenrec plasma for post-translational protein citrullination profiles (citrullinomes) and extracellular vesicle (EV) characteristics, including selected microRNA cargoes (miR-21, miR-155, miR-206, miR-210), between baseline active and hibernating states at low (12 °C) and high (28 °C) ambient temperatures. Our findings show considerable changes in citrullinome plasma profiles and associated Gene Ontology and KEGG pathway analysis linked to physiological and inflammatory processes, comparing hibernating and active states, also differing between the two ambient temperature groups. We furthermore identified modified EV profiles with respect to stress-related (miR-21, miR-155), hypoxia (miR-210) and metabolic/muscle related (miR-206) microRNA cargoes, which showed significant differences between active and hibernating animals, also comparing the two ambient temperature groups. Our findings show novel roles for post-translational protein citrullination in regulating immune and metabolic associated pathways in the tenrec, and highlight EV profiles, based on microRNA cargoes, as indicators for stress and metabolic responses in active versus hibernating states, including at different temperatures. Collectively our data highlights the tenrec as an evolutionary model for regulating pathobiological responses in extreme environments and may have translatable potential for human physiology and pathologies. Full article

Background/Objectives: Neutrophils have recently gained significant attention due to their heterogeneity in tumor settings. Recent data showed neutrophil pro- and anti-tumor profiles during tumor progression. However, the concessive causes of neutrophil skewing toward one or another profile are not fully understood. Methods: In this study, using RT-qPCR, flowcytometry, and confocal microscopy, we investigated the phenotype of splenic neutrophils of mice bearing Lewis lung carcinoma LLC, RLS₄₀ lymphosarcoma, and B16 melanoma. Results: Our data showed an immunosuppressive phenotype in the case of the LLC model with PD-L1 and IL10 expression. In the B16 model, minimal changes in the neutrophil phenotype were observed, regardless of tumor size. In the RLS₄₀ model, the neutrophil phenotype was associated with the tumor growth rate, where, in aggressively progressed tumors (RLS₄₀^High), CCL17 was expressed, while, in mice with controlled tumor growth (RLS₄₀^Low), anti-tumor markers were expressed (FAS, ICAM-1, PD-L1). DNase I treatment significantly reduced tumor growth and metastasis in the RLS₄₀ model but not in B16, enhanced the anti-tumor profile in RLS₄₀ neutrophils, and tended to reduce NET formation induced by A23187. Conclusions: The phenotype of neutrophils from tumor-bearing mice is influenced by the tumor type and progression stage. DNase I had anti-tumor, antimetastatic, and immunostimulatory effects and significantly modified the neutrophil profile in the immunogenic model RLS₄₀. 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

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

Introduction: Accumulating evidence indicates that neutrophils undergo reprogramming of their effector functions as they migrate from the bloodstream into an inflamed tissue. Here, we examined the role of the small ubiquitin-like modifier (SUMO) conjugation in modulating neutrophil functional changes in the inflammatory microenvironment. Methods: Primary human and murine neutrophils were used to assess SUMOylation levels in vitro by Western blotting and results were validated in clinical samples from patients undergoing surgery involving hypothermic circulatory arrest. SUMOylation was inhibited with TAK-981, and its impact on neutrophil migration, NETosis, and phagocytosis was assessed in vitro. The in vivo effect of TAK-981 on neutrophil tissue infiltration was further evaluated using a sterile sponge assay in mice. Results: Our results demonstrated that neutrophil SUMOylation was induced by factors of the inflammatory microenvironment (temperature and oxidative stress) and inflammatory stimulants in vitro, and under conditions of general inflammatory activation in patients. Further, we found that blocking SUMOylation with TAK-981 in vitro blunted neutrophil migration and phagocytosis but did not affect NETosis. Notably, TAK-981 treatment reduced neutrophil accumulation in sterile sponges in mice. Conclusions: Our work identifies SUMOylation as a novel mechanism of neutrophil tissue reprogramming. Blocking SUMOylation may provide a therapeutic option to limit the contribution of neutrophils to inflammation-associated tissue damage. 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 remains a critical global health challenge characterized by life-threatening organ dysfunction arising from a dysregulated host response to infection. Immunothrombosis refers to the intersection of immune activation and coagulation pathways, particularly relevant in the context of sepsis. A growing body of evidence identifies immunothrombosis, a tightly interwoven process between innate immunity and coagulation. While immunothrombosis serves as a host defense mechanism under physiological conditions, its aberrant activation in sepsis precipitates microvascular thrombosis, organ ischemia, and progression toward disseminated intravascular coagulation (DIC). This review provides a comprehensive overview of the cellular contributors to immunothrombosis, including neutrophils, monocytes, platelets, and endothelial cells, and elucidates the signaling cascades, such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and inflammasome activation, that govern their interplay. We further highlight emerging molecular mediators, including extracellular traps, tissue factor expression, and cytokine amplification loops, that collectively promote pathological thromboinflammation. A deeper understanding of these interconnected pathways offers critical insights into the pathogenesis of sepsis and unveils potential targets for timely intervention. Ultimately, this review aims to bridge immunological and hematological perspectives to inform the development of novel therapeutic strategies against sepsis-induced coagulopathy. Full article