Immunological Functions Research Articles

B7-H3 suppresses CD8+ T cell immunologic function through reprogramming glycolytic metabolism.

Malignant neoplasms pose a formidable threat to human well-being. Prior studies have documented the extensive expression of B7 homolog 3 (B7-H3 or CD276) across various tumors, affecting glucose metabolism. Yet, the link between metabolic modulation and immune responses remains largely unexplored. Our study reveals a significant association between B7-H3 expression and advanced tumor stages, lymph node metastasis, and tumor location in oral squamous cell carcinoma (OSCC). We further elucidate B7-H3's role in mediating glucose competition between cancer cells and CD8+ T cells. Through co-culturing tumor cells with flow cytometry-sorted CD8+ T cells, we measured glucose uptake and lactate secretion in both cell types. Additionally, we assessed interferon-gamma (IFN-γ) release and the immune and exhaustion status of CD8+ T cells. Our findings indicate that B7-H3 enhances glycolysis in OSCC and malignant melanoma, while simultaneously inhibiting CD8+ T cell glycolysis. Silencing B7-H3 led to increased IFN-γ secretion in co-cultures, highlighting its significant role in modulating CD8+ T cell functions within the tumor microenvironment and its impact on tumorigenicity. We also demonstrate that glycolysis inhibition can be mitigated by exogenous glucose supplementation. Mechanistically, our study suggests B7-H3's influence on metabolism might be mediated through the phosphoinositide3-kinase (PI3K)/ protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway. This research unveils how B7-H3 affects immune functions via metabolic reprogramming.

Neoself Antigens Presented on MHC Class II Molecules in Autoimmune Diseases.

Major histocompatibility complex (MHC) class II molecules play a crucial role in immunity by presenting peptide antigens to helper T cells. Immune cells are generally tolerant to self-antigens. However, when self-tolerance is broken, immune cells attack normal tissues or cells, leading to the development of autoimmune diseases. Genome-wide association studies have shown that MHC class II is the gene most strongly associated with the risk of most autoimmune diseases. When misfolded self-antigens, called neoself antigens, are associated with MHC class II molecules in the endoplasmic reticulum, they are transported by the MHC class II molecules to the cell surface without being processed into peptides. Moreover, neoself antigens that are complexed with MHC class II molecules of autoimmune disease risk alleles exhibit distinct antigenicities compared to normal self-antigens, making them the primary targets of autoantibodies in various autoimmune diseases. Elucidation of the immunological functions of neoself antigens presented on MHC class II molecules is crucial for understanding the mechanism of autoimmune diseases.

Investigations into the Immunological Functions of LILRB3 and Its Association with Human Malignancies

Investigations into the Immunological Functions of LILRB3 and Its Association with Human Malignancies

Dynamical analysis of COVID-19 and tuberculosis co-infection using mathematical modelling approach

<abstract><p>Both tuberculosis (TB) and COVID-19 are infectious diseases with similar clinical manifestations, which mainly affect the lungs. Clinical studies have revealed that the immunosuppressive drugs taken by COVID-19 patients can affect the immunological functions in the body, which can cause the patients to contract active TB via a new infection or reinfection, and the co-infection of the two diseases portends a clinical complexity in the management of the patients. Thus, this paper presents a mathematical model to study the dynamics and control of COVID-19-TB co-infection. The full model of the co-infection is split into two submodels, namely, the TB-only and the COVID-19-only models. The equilibria of the disease-free and endemic situations of the two sub-models are shown to be globally asymptotically stable when their control reproduction numbers $ R_{o}^{TV}, R_{o}^{CV} < 1 $ and $ \tilde {R}_{o}^{TV}, \tilde {R}_{o}^{CV} > 1 $, respectively. However, the disease-free equilibrium of the co-infection model was found to lose its global stability property when the reproduction number $ R_{o}^{F} < 1 $, therefore exhibiting a backward bifurcation. Uncertainty and sensitivity analysis of the associated reproduction number of the full model has been performed by using the Latin hypercube sampling/Pearson rank correlation coefficient (LHS/PRCC) method. The rate of transmission of COVID-19 and the proportions of individuals vaccinated with Bacillus Calmette-Guérin (BCG) and against COVID-19 were found to be highly significant in the spread and control of COVID-19-TB co-infection. Furthermore, the simulation results show that decreasing the COVID-19 transmission rate and increasing the proportion of people vaccinated with BCG and against COVID-19 can lower the number of cases of COVID-19-TB co-infection. Therefore, measures to reduce the transmission rate and the provision of adequate resources to increase the proportions of people vaccinated against TB and COVID-19 should be implemented to minimize the cases of co-infection.</p></abstract>

Proteomic and transcriptomic analyses identify apo-transcobalamin-II as a biomarker of overall survival in osteosarcoma.

The large-scale proteomic platform known as the SomaScan® assay is capable of simultaneously measuring thousands of proteins in patient specimens through next-generation aptamer-based multiplexed technology. While previous studies have utilized patient peripheral blood to suggest serum biomarkers of prognostic or diagnostic value in osteosarcoma (OSA), the most common primary pediatric bone cancer, they have ultimately been limited in the robustness of their analyses. We propose utilizing this aptamer-based technology to describe the systemic proteomic milieu in patients diagnosed with this disease. To determine novel biomarkers associated with overall survival in OSA, we deployed the SomaLogic SomaScan® 7k assay to investigate the plasma proteomic profile of naive primary, recurrent, and metastatic OSA patients. Following identification of differentially expressed proteins (DEPs) between 2-year deceased and survivor cohorts, publicly available databases including Survival Genie, TIGER, and KM Plotter Immunotherapy, among others, were utilized to investigate the significance of our proteomic findings. Apo-transcobalamin-II (APO-TCN2) was identified as the most DEP between 2-year deceased and survivor cohorts (Log2 fold change = 6.8, P-value= 0.0017). Survival analysis using the Survival Genie web-based platform indicated that increased intratumoral TCN2 expression was associated with better overall survival in both OSA (TARGET-OS) and sarcoma (TCGA-SARC) datasets. Cell-cell communication analysis using the TIGER database suggested that TCN2+ Myeloid cells likely interact with marginal zone and immunoglobin-producing B lymphocytes expressing the TCN2 receptor (CD320) to promote their proliferation and survival in both non-small cell lung cancer and melanoma tumors. Analysis of publicly available OSA scRNA-sequencing datasets identified similar populations in naive primary tumors. Furthermore, circulating APO-TCN2 levels in OSA were then associated with a plasma proteomic profile likely necessary for robust B lymphocyte proliferation, infiltration, and formation of intratumoral tertiary lymphoid structures for improved anti-tumor immunity. Overall, APO-TCN2, a circulatory protein previously described in various lymphoproliferative disorders, was associated with 2-year survival status in patients diagnosed with OSA. The relevance of this protein and apparent immunological function (anti-tumor B lymphocyte responses) was suggested using publicly available solid tumor RNA-sequencing datasets. Further studies characterizing the biological function of APO-TCN2 and its relevance in these diseases is warranted.

IL-15 in T-Cell Responses and Immunopathogenesis.

IL-15 belongs to the common gamma chain cytokine family and has pleiotropic immunological functions. IL-15 is a homeostatic cytokine essential for the development and maintenance of NK cells and memory CD8+ T cells. In addition, IL-15 plays a critical role in the activation, effector functions, tissue residency, and senescence of CD8+ T cells. IL-15 also activates virtual memory T cells, mucosal-associated invariant T cells and γδ T cells. Recently, IL-15 has been highlighted as a major trigger of TCR-independent activation of T cells. This mechanism is involved in T cell-mediated immunopathogenesis in diverse diseases, including viral infections and chronic inflammatory diseases. Deeper understanding of IL-15-mediated T-cell responses and their underlying mechanisms could optimize therapeutic strategies to ameliorate host injury by T cell-mediated immunopathogenesis. This review highlights recent advancements in comprehending the role of IL-15 in relation to T cell responses and immunopathogenesis under various host conditions.

Multi-omics pan-cancer analysis reveals the prognostic values and immunological functions of PPA2, with a spotlight on breast cancer.

Recently, the role of inorganic pyrophosphatase 2 (PPA2) has been remaining merely superficial in many tumors. Hence, the aim was to analyze the potential functions of PPA2 in pan-cancer, focusing on its role in breast cancer. A systematic pan-cancer analysis conducted primarily utilizing various open databases such as TCGA and GTEx. We explored the clinical value of PPA2 as well as various biological functions, including expression levels and subcellular localization, multi-dimensional immune-correlation analysis, co-expression networks, and gene heterogeneity. In addition, we not only verified the function of PPA2 through cell experiments but also analyzed PPA2 at the single-cell level and its drug sensitivity. PPA2 is abnormally expressed in various tumors, and it is mainly distributed in mitochondria. Furthermore, the indicators (OS, DSS, DFI, and PFI) of analysis hint that PPA2 exhibits significant prognostic value. At the same time, the genomic heterogeneity (including TMB, MSI, MATH, and NEO) of PPA2 in pan-cancer was analyzed. Across multiple tumors, the results showed a close correlation between PPA2 expression levels and different immune signatures (such as immune cell infiltration). All of these indicate that PPA2 could potentially be applied in the guidance of immunotherapy. We also have demonstrated that PPA2 promoted the process of breast cancer. Finally, some potential therapeutic agents (such as Fulvestrant) targeting the abnormal expression of PPA2 are revealed. In conclusion, the results demonstrated the great value of PPA2 in pan-cancer research, as well as its potential as a therapeutic target for breast tumors.

Lactobacillus reuteri's multifaceted role in mitigating ionizing radiation-induced injury in Drosophila melanogaster.

The numerous beneficial probiotic properties of Lactobacillus reuteri (L. reuteri) include decreasing metabolic syndrome, preventing disorders linked to oxidative stress, improving gut flora imbalances, controlling immunological function, and extending life span. Exposure to ionizing radiation is closely associated with several disorders. We examined the protective and salvaging effects of L. reuteri on ionizing radiation-induced injury to the intestinal tract, reproductive system, and nervous system of Drosophila melanogaster. We also examined its effects on lifespan, antioxidant capacity, progeny development, and behavioral aspects to assess the interaction between L. reuteri and ionizing radiation-induced injury. The findings demonstrated that L. reuteri improved the median survival time following irradiation and greatly extended its lifespan. In addition, it raised SOD activity, reduced ROS levels in intestinal epithelial cells, and increased the quantity of intestinal stem cells. Furthermore, L. reuteri enhanced the adult male flies' capacity to move. It also successfully safeguarded the generations' growth and development. L. reuteri dramatically enhanced expression of the AMPKα gene and regulated expression of its pathway-related gene, mTOR, as well as the autophagy-related genes Atg1 and Atg5 in female Drosophila exposed to irradiation. Notably, no prior reports have been made on the possible effects of L. reuteri on injuries caused by irradiation. As a result, our research offers important new information regarding L. reuteri's possible role as a shield against ionizing radiation-induced injury.

The Inflammation-Induced Dysregulation of Reelin Homeostasis Hypothesis of Alzheimer's Disease.

Alzheimer's disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation.

HIV-1 Induced Cell-to-Cell Fusion orSyncytium Formation.

HIV-1 cell-free infection has been thoroughly investigated; however, its relevance and importance in vitro are questionable. Cell-cell transmission is now thought to be the dominant mode of transmission within the host; however precise molecular details remain elusive. The considerable potency of cell-cell transmission hinges upon its ability to hijack and manipulate host immunological function to target uninfected cells, along with overcoming restriction factors and increasing the speed of latent pool formation. Another question of relevance is virus induced cell-cell fusion and how this process is regulated. How often HIV-1 induces the formation of syncytia? Is cell-cell function a potential process for HIV-1 transmission? These questions are discussed and reviewed together with a description of the most common ways of HIV-1 entry and transinfection.

Data-lndependent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Salivary Biomarkers of Primary Sjogren's Syndrome

Objective As primary Sj?gren's syndrome (pSS) primarily affects the salivary glands, saliva can serve as an indicator of the glands' pathophysiology and the disease's status. This study aims to illustrate the salivary proteomic profiles of pSS patients and identify potential candidate biomarkers for diagnosis.Methods The discovery set contained 49 samples (24 from pSS and 25 from age- and gender-matched healthy controls [HCs]) and the validation set included 25 samples (12 from pSS and 13 from HCs). Totally 36 pSS patients and 38 HCs were centrally randomized into the discovery set or to the validation set at a 2:1 ratio. Unstimulated whole saliva samples from pSS patients and HCs were analyzed using a data-independent acquisition (DIA) strategy on a 2D LC?HRMS/MS platform to reveal differential proteins. The crucial proteins were verified using DIA analysis and annotated using gene ontology (GO) and International Pharmaceutical Abstracts (IPA) analysis. A prediction model for SS was established using random forests.Results A total of 1,963 proteins were discovered, and 136 proteins exhibited differential representation in pSS patients. The bioinformatic research indicated that these proteins were primarily linked to immunological functions, metabolism, and inflammation. A panel of 19 protein biomarkers was identified by ranking order based on P-value and random forest algorichm, and was validated as the predictive biomarkers exhibiting good performance with area under the curve (AUC) of 0.817 for discovery set and 0.882 for validation set.Conclusions The candidate protein panel discovered may aid in pSS diagnosis. Salivary proteomic analysis is a promising non-invasive method for prognostic evaluation and early and precise treatments for pSS patients. DIA offers the best time efficiency and data dependability and may be a suitable option for future research on the salivary proteome.

Medicinal Importance of Solanum nigrum Linn; A Review

Solanum nigrum (Black nightshade) is an indigenous medicinal plant that has been utilized in traditional medical systems for ages. S. nigrum includes bioactive substances such as alkaloids, flavonoids, steroids, and saponins, according to phytochemical research. Extracts and isolated chemicals indicate antioxidant, anti-inflammatory, antibacterial, antifungal, anti-diabetic, anti-cancer, immune-stimulating, therapeutic, and heart-protective effects. S. nigrum extracts, in particular, limit cancer cell growth, minimize chemically induced organ damage, alter immunological function, and provide protection against oxidative stress, according to animal and cell culture studies. S. nigrum has traditionally been used for the prevention of symptoms such as discomfort, inflammation, infections, and problems with the gastrointestinal tract. Overall, this comprehensive study reveals the varied therapeutic qualities of S. nigrum that demand further exploration.

Characterization of novel HLA-A*24:608N allele discovered in Koreans.

A novel null HLA-A*24 allele, HLA-A*24:608N, was identified in five Korean subjects including three from a family and two separate individuals. This study was performed to discern its immunological function in transplantation settings. Because this null variant had deletions of approximately 12 k base pairs from intron 3 to 3' end of the HLA-A gene, low resolution HLA typing and amplicon-based next generation sequencing (NGS) typing methods had failed to assign it. Hybrid capture-based NGS method confirmed that this novel variant had a large deletion. T-lymphocyte crossmatching by complement-dependent lymphocytotoxicity and flow cytometry with a serum consisting anti-HLA-A24 antibody revealed negative results, implying that an individual with this allele would not carry a functioning A24 antigen. These findings highlight the importance of identifying a null HLA allele by employing appropriate molecular method and providing expected crossmatching outcomes in a real-world transplantation setting.

CsIL-20, a tongue sole interleukin-20, negatively mediates leucocyte activity and antibacterial defense

Interleukin-20 (IL-20), as an essential member of IL-10 family, plays vital roles in mammalian immunological response such as antimicrobial, inflammation, hematopoiesis, and immune diseases. In teleost, the study about immune antimicrobial function of IL-20 is largely scarce. In this article, we revealed the expression profiles and the immunological functions of the IL-20 (CsIL-20) in tongue sole Cynoglossus semilaevis. CsIL-20 is composed of 183 amino acid residues, with seven cysteine residues and a typical IL-10 domain which comprises six α-helices and two β-sheets, and shares 34.4–71.2 % identities with other teleost IL-20. CsIL-20 was constitutively expressed in a variety of tissues and regulated by bacterial invasion, and the recombinant CsIL-20 (rCsIL-20) could bind to different bacteria. In vitro rCsIL-20 could interact with the membrane of peripheral blood leukocytes (PBLs), leading to the attenuation of reactive oxygen species (ROS) production and acid phosphatase activity in PBLs. In line with In vitro results, In vivo rCsIL-20 could obviously suppressed the host immune against bacterial infection. Furthermore, knockdown of CsIL-20 in vivo could markedly enhance the host antibacterial immunity. Collectively, these observations offer new insights into the negative effect of CsIL-20 on antibacterial immunity.

Antimicrobial Activity of Human C-Type Lectin Domain Family 3 Member A (CLEC3A)

C-type lectins (CTLs) are a group of proteins that play a crucial role in immunological functions. With the rise of antibiotic-resistant bacteria, CTLs have emerged as a potential alternative to traditional antibiotics and antimicrobial peptides (AMPs), the latter exhibiting limited application due to their low biostability. In this study, we used viable count assays to investigate the antimicrobial activity of the human C-type Lectin Domain Family 3 Member A (CLEC3A) and its two protein domains, CLEC3A Ex23 and CLEC3A Ex3, against gram-positive and gram-negative bacteria. Additionally, using immunoblot analysis, we assessed the biostability of CLEC3A and its protein domains in bacterial supernatant and murine serum. Our findings demonstrate that CLEC3A, CLEC3A Ex23, and CLEC3A Ex3 possess antimicrobial activity against gram-positive Staphyloccocus aureus and gram-negative Pseudomonas aeruginosa. CLEC3A is more effective against P. aeruginosa than the well-investigated antimicrobial peptide LL-37. Furthermore, CLEC3A and its domains have low sensitivity to bacterial and serum proteases, making them more advantageous for systemic application than most AMPs. In conclusion, our research has demonstrated that CLEC3A is not only a precursor of AMPs but also an antimicrobial protein itself, with favorable characteristics for therapeutic applications.

Inferring secretory and metabolic pathway activity from omic data with secCellFie

Understanding protein secretion has considerable importance in biotechnology and important implications in a broad range of normal and pathological conditions including development, immunology, and tissue function. While great progress has been made in studying individual proteins in the secretory pathway, measuring and quantifying mechanistic changes in the pathway's activity remains challenging due to the complexity of the biomolecular systems involved. Systems biology has begun to address this issue with the development of algorithmic tools for analyzing biological pathways; however most of these tools remain accessible only to experts in systems biology with extensive computational experience. Here, we expand upon the user-friendly CellFie tool which quantifies metabolic activity from omic data to include secretory pathway functions, allowing any scientist to infer properties of protein secretion from omic data. We demonstrate how the secretory expansion of CellFie (secCellFie) can help predict metabolic and secretory functions across diverse immune cells, hepatokine secretion in a cell model of NAFLD, and antibody production in Chinese Hamster Ovary cells.

Effect of age and season on respiratory mucosal immune marker profiles

BackgroundThe upper respiratory tract is continuously exposed to microorganisms and noxious elements, leading to local immune responses and the secretion of immune markers. While several studies describe immune marker profiles in respiratory mucosal samples in defined patient cohorts, mucosal immune profiles from the general population during the different seasons are lacking. Such baseline profiles are essential to understand the impact of various exposures to the mucosal immune system throughout life. ObjectivesTo establish baseline, local upper respiratory mucosal immune profiles in the general population, and assess these profiles in regard to age, sex, seasonality, and basic health and lifestyle factors. MethodsWe measured the concentrations of 35 immune markers involved in a broad range of immunological processes at the mucosa in nasopharyngeal swab samples from 951 individuals from a nationwide study, aged 0-86 years. ResultsClustering analysis shows that the immune marker profiles clearly reflect immunological functions, such as tissue regeneration and antiviral responses. The concentrations of the immune markers changed strongly with seasonality and age -with the most profound changes occurring in the first 25 years of life- and also associated with sex, BMI, smoking, mild symptoms of airway infection, and chronic asthma and hay fever. ConclusionWe show that immunological analyses of non-invasive mucosal samples provide insight into mucosal immune responses to microbial and noxious element exposure in the general population. These data provide a baseline for future studies on respiratory mucosal immune responses and for the development of mucosal immune-based diagnostics.

Serum albumin mediates the associations between heavy metals and two novel systemic inflammation indexes among U.S. adults

BackgroundThe effects of heavy metal exposure on immunological function have sparked widespread concern, but unequivocal evidence on the association between mixed metal exposure and novel systemic inflammatory indexes remains scarce. ObjectivesThis study aimed to analyze the associations of heavy metals with two novel systemic inflammation indexes and the mediated effects of serum albumin. MethodsNineteen metals were detected among 4082 U.S. adults based on the NHANES. A linear regression, restricted cubic splines (RCS) regression, weighted quantile sum (WQS), Quantile-based Gcomputation (qgcomp), and Bayesian kernel machine regression (BKMR) were conducted to evaluate the associations of single metal and mixed metals with systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) levels, respectively. A series of subgroup analyses were used to identify potentially vulnerable populations. Furthermore, we conducted mediation analyses to investigate the mediated effects of serum albumin on the associations of metals with SII and SIRI. ResultsIn the single-exposure model, exposure to various metals such as urinary Co, As, and serum Zn, Cu was associated with SII and SIRI (PFDR<0.05). Simultaneously, the above metals were linear positively correlated with SII and SIRI. Mixed-exposure analyses consistently showed that overall mixed urinary metal levels were positively pertinent for SII and SIRI levels, and the metal Co played a significant role in the urinary metal mixtures. Subgroup analyses showed that exposure to urinary Cd in men and elderly people increased SII and SIRI levels. The results of mediation analyses suggested the association of urinary metal mixture with SII and SIRI was mediated by albumin, and the proportion of mediation was 14.45% and 9.49%, respectively. ConclusionsOur findings suggested that metal exposure is strongly associated with the levels of system inflammation indexes and that serum albumin is, in part, a mediator of this association.

Genomic analysis in the colon tissues of omega-3 fatty acid-treated rats identifies novel gene signatures implicated in ulcerative colitis

Several long-term intervention trials only studied the ex vivo immunological function to elucidate the beneficial mechanisms of n-3 polyunsaturated fatty acids (PUFA) in the ulcerative colitis (UC). An unbiased whole-transcriptome analysis would be more valuable to obtain a comprehensive understanding of the processes and genes regulated by n-3 PUFA in vivo. In this study, we have performed microarray analysis in the colon tissues of dextran sulfate sodium (DSS)-induced UC in rats supplemented with n-6 PUFA, n-3PUFA and long-chain n-3PUFA (LC-n3PUFA). We have identified the novel gene signatures previously not linked to colitis such as Etv3, Clec4d, CD180, CD72, Megf11, and Angptl4 which are most downregulated in both n-3PUFA and LC-n3PUFA groups compared to the n-6PUFA group. The most upregulated genes were Nr1i3, Nptx2, and Zfp810 in both n-3PUFA and LC-n3PUFA groups. The RT-PCR analysis confirmed similar results. Interestingly, LPS treatment in macrophages upregulated the Megf11, Etv3, CD180, and Angptl4, and correlated with increased secretion of cytokines. Gene silencing of Etv3, Megf11, and CD180 in rats using intravascular delivery of siRNA-lipoparticles attenuated the DSS-induced ulceration and mucosal damage. Thus, our genome-wide microarray analysis identified novel genes regulated by omega-3 PUFA and offers new drug targets that could prevent or reduce UC.

To Gain Insights into the Pathophysiological Mechanisms of the Thrombo-Inflammatory Process in the Atherosclerotic Plaque.

Thromboinflammation, the interplay between thrombosis and inflammation, is a significant pathway that drives cardiovascular and autoimmune diseases, as well as COVID-19. SARS-CoV-2 causes inflammation and blood clotting issues. Innate immune cells have emerged as key modulators of this process. Neutrophils, the most predominant white blood cells in humans, are strategically positioned to promote thromboinflammation. By releasing decondensed chromatin structures called neutrophil extracellular traps (NETs), neutrophils can initiate an organised cell death pathway. These structures are adorned with histones, cytoplasmic and granular proteins, and have cytotoxic, immunogenic, and prothrombotic effects that can hasten disease progression. Protein arginine deiminase 4 (PAD4) catalyses the citrullination of histones and is involved in the release of extracellular DNA (NETosis). The neutrophil inflammasome is also required for this process. Understanding the link between the immunological function of neutrophils and the procoagulant and proinflammatory activities of monocytes and platelets is important in understanding thromboinflammation. This text discusses how vascular blockages occur in thromboinflammation due to the interaction between neutrophil extracellular traps and ultra-large VWF (von Willebrand Factor). The activity of PAD4 is important for understanding the processes that drive thromboinflammation by linking the immunological function of neutrophils with the procoagulant and proinflammatory activities of monocytes and platelets. This article reviews how vaso-occlusive events in thrombo-inflammation occur through the interaction of neutrophil extracellular traps with von Willebrand factor. It highlights the relevance of PAD4 in neutrophil inflammasome assembly and neutrophil extracellular traps in thrombo-inflammatory diseases such as atherosclerosis and cardiovascular disease. Interaction between platelets, VWF, NETs and inflammasomes is critical for the progression of thromboinflammation in several diseases and was recently shown to be active in COVID-19.