Acute lung injury (ALI) is a life-threatening pulmonary inflammatory disorder with high morbidity and mortality rates. Effective targeting of damaged lung tissues and regulation of inflammatory dysregulation are major challenges in clinical treatment. This study aimed to develop a multifunctional drug delivery system by coating mesoporous polydopamine nanoparticles (mPDA NPs) loaded with Peimine (PM) using macrophage membranes (MMs) to leverage their inflammatory targeting properties. Both in vitro and in vivo experiments demonstrated the excellent targeting capability, strong antioxidant activity, and significant anti-inflammatory effects of the developed MM@mPDA-PM NPs. Furthermore, transcriptomics analysis revealed that MM@mPDA-PM NPs significantly reduced myeloperoxidase (MPO), neutrophil elastase (NE), and peptidylarginine deiminase 4 (PAD4), as well as inhibited the formation of neutrophil extracellular traps (NETs), and promoted M2 macrophage polarization by downregulating the NF-κB and JAK/STAT pathways. Our developed system effectively reduced neutrophil infiltration, suppressed cytokine storms, and regulated the pulmonary immune microenvironment, demonstrating great potential for treating ALI and other inflammatory diseases.

Neutrophil extrusion of neutrophil extracellular traps (NETs) in a process called NETosis provides immune defense against extracellular bacteria. It has been observed that bacteria are capable of activating neutrophils to release NETs that subsequently kill them or at least prevent their local spread within host tissue. However, existing studies have mainly focused on the isolated function of NETs, with less attention given to their anti-bacterial mechanisms through interactions with other immune cell populations. The net effect of these complex intercellular interactions, which may act additively, synergistically, or antagonistically, is a critical determinant in the outcomes of host-pathogen interactions. This review summarizes the mechanisms underlying classic NET formation and their crosstalk with the immune system, offering novel insights aimed at balancing the anti-microbial function with their potential inflammatory risks.

Heavy alcohol consumption is implicated in the alteration of the antimicrobial function of neutrophils, such as phagocytosis, chemotaxis, the formation of neutrophil extracellular traps (NETs), and the occurrence of NETosis. NETosis is an endogenous process of elimination of invading microbes, autoantibodies, and inflammatory elements such as danger-associated molecular patterns (DAMPs) and pathogen-associated patterns (PAMPs). However, both exaggeration and suppression of NETosis modulate normal physiological and metabolic processes by influencing events at the molecular and cellular levels. Recent research shows that binge alcohol consumption induces NETosis, leading to tissue damage and inflammation. Binge alcohol consumption, chronic alcohol intake, and alcohol use disorder (AUD) can affect immunity and often lead to alcohol-associated liver disease (ALD) and/or other organ damage. Alcohol can lead to detrimental consequences in multiple organs, including the brain, liver, pancreas, and gut. Gut-derived microbial substances, such as endotoxins in the circulation, induce systemic inflammation. Sterile danger signals from damaged cells, cytokines, and prostaglandins act as proinflammatory stimuli and are involved in multiple signaling pathways. The alcohol-induced proinflammatory cytokines chemoattract neutrophils, which interact and coordinate with other immune cells to exaggerate or suppress inflammation within the inflammatory milieu, depending on the alcohol effects. Several proteins, including different receptors, play important roles in the activation and formation of NETs as well as the initiation and execution of NETosis. This review article specifically gathers the current information on NETosis, its biological components, and signaling pathways relating to the formation of NETs and the occurrence of NETosis associated with ALD and AUD in multiorgans, specifically in the brain, liver, and gut. We also briefly describe various therapeutic strategies against AUD-associated NETosis in experimental models and human disease states.

Neutrophils, as first-line immune cells, typically lose their edge within the diabetic wounds accompanied by methicillin-resistant Staphylococcus aureus (MRSA) infections (the D/M setting), playing the role of "more foe than friend" during the healing process. Specifically, reduced influx of calcium ions (Ca2+) and impaired calcium homeostasis yield the dysfunction of neutrophil sequential behaviors in pathogen killing and wound healing, manifesting as suppressed chemotaxis, decreased intracellular reactive oxygen species (ROS) generation, prolonged apoptosis, and retention of neutrophil extracellular traps (NETs). To address this challenge, this study fabricated potassium (K)-doped manganese dioxide nanoparticles (MnO2 NPs), which activated transmembrane Ca2+ channels by inducing neutrophil depolarization via electron transfer. Subsequently, this contributed to the initial Ca2+ influx and reprogrammed Ca2+-dependent behaviors of impaired neutrophils. Also, the potential antimicrobial capacity of K-MnO2 NPs created a favorable extracellular environment that restored calcium homeostasis, enabling apoptotic neutrophils to be removed timely. Therefore, the wounds treated with K-MnO2 NPs in the D/M setting exhibited potent resistance to MRSA and rapid healing, which could be attributed to the synergistic effects of K-MnO2 NPs in leveraging Ca2+ influx and maintaining calcium homeostasis. In brief, K-MnO2 NPs constitute an effective strategy to resist MRSA and rapid wound healing in the D/M setting.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome, and the incidence of invasive fungal infection (IFI) among hospitalized patients with ACLF is steadily increasing. The aim of this study is to develop a diagnostic nomogram to assist in the identification of IFI in these patients.

A retrospective study included 705 patients from January 1, 2019, to October 31, 2023, randomly divided into training (n = 493) and validation (n = 212) cohorts. The diagnosis of IFI includes proven diagnosis and probable diagnosis. Kaplan analysis was performed to analyze the survival prognosis of ACLF patients with and without IFI. A nomogram was developed based on a logistic regression model derived through least absolute shrinkage and selection operator (LASSO) regression. The discrimination, accuracy, and clinical utility of the model were assessed using receiver operating characteristic curves, Hosmer-Lemeshow tests, calibration plots, and decision curve analysis.

Kaplan-Meier survival analysis confirmed that the median survival time of ACLF patients with IFI was significantly lower (by 68 days) than that of ACLF patients without IFI, and there were significant differences in the 90-day, 180-day, and 360-day survival rates between the two groups (P < 0.05). Based on LASSO regression, the following factors were identified as significant risk factors for predicting IFI: aminotransferase levels, prothrombin activity, hemoglobin, neutrophil-to-lymphocyte ratio, and serum total bilirubin. A nomogram was constructed incorporating these variables. The nomogram demonstrated good discriminative ability, with an area under the receiver operating characteristic curve (AUC) of 0.78 (95% confidence interval [CI]: 0.72-0.84) in the training cohort and 0.79 (95% CI: 0.70-0.87) in the validation cohort. Decision curve analysis further validated the clinical applicability of the nomogram.

ACLF patients with IFI have lower survival time than those without IFI. A nomogram was developed and validated to assist clinicians in the early prediction of IFI in hospitalized patients with ACLF.

Not applicable.

Neutrophils are the first line of defense against pathogens, most effectively by forming Neutrophil Extracellular Traps (NETs). Neutrophiles are further classified into several subpopulations during their development, eliminating pathogens through various mechanisms. However, due to the chaotic and uncontrolled immune response, NETs are often severely resulting in tissue damage and lung infections. The uncontrolled and poorly acknowledged host response regarding the cytokine storm is one of the major causes of severe COVID-19 conditions. Specifically, the increased formation of low-density neutrophils (LDNs), together with neutrophil extracellular traps (NETs) is closely linked with the severity and poor prognosis in patients with COVID-19. In this review, we discuss in detail the ontogeny of neutrophils at different stages and their recruitment and activation after infections, focusing on SARS-CoV-2. In addition, this chapter summarized the research progress on potential targeted drugs (NETs and Cytokine inhibitors) for neutrophil medical therapy and hoped to provide reference for the development of related therapeutic drugs for critically ill COVID-19 patients.

Streptococcus anginosus is considered an emerging opportunistic pathogen causing life-threatening infections, including abscesses and empyema. Noticeably, clinical data revealed that S. anginosus also constitutes an important component of polymicrobial infections. Here, we showed for the first time that S. anginosus inactivates the antibacterial potential of neutrophil extracellular traps (NETs). The process is determined by a cell wall-anchored nuclease referred to as SanA, which high expression dominates in clinical strains isolated from severe infections. Nuclease activity protects S. anginosus against the antibacterial activity of NETs, supporting at the same time the survival of coexisting highly pathogenic species of Enterobacteriales. Obtained data suggest that SanA nuclease should be recognized as a critical S. anginosus virulence factor determining severe monospecies purulent infections but also shielding other pathogens promoting the development of polymicrobial infections.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease that is challenging to treat. This study aimed to identify the effect of sodium ferulate on endothelial dysfunction mediated by neutrophil extracellular trap (NET)-platelet activation in AAV to provide potential strategies for AAV treatment.

An animal model of myeloperoxidase (MPO)-AAV passive immune vasculitis was established using anti-MPO immunoglobulin G and Rag2 knockout mice. The efficacy and mechanism of action of sodium ferulate in AAV were explored in cultured and isolated endothelial progenitor cells (EPCs), and messenger ribonucleic acid gene expression, relative protein expression, and protein fluorescence intensity were determined through quantitative polymerase chain reaction, Western blotting, and immunofluorescence, respectively. Serum antibody concentrations were determined by enzyme-linked immunosorbent assay, and flow cytometry was used in determining the expression levels of platelet-selectin (CD62p) and procaspase-activating compound-1 (PAC-1) on the surfaces of the platelets. The EPCs' ultramicroscopic structure was observed through transmission electron microscopy.

The expression levels of ANCA, histone H3 citrullinated, and MPO protein fluorescence intensity in MPO-AAV mice were inhibited by sodium ferulate, and the expression levels of CD62p and PAC-1 on the cell surface were reduced. The relative expression levels of β-trace protein (β-TG), soluble thrombomodulin, inducible nitric oxide synthase (iNOS), and tumor necrosis factor α decreased. We found that sodium ferulate inhibited NETs' free DNA and mitigated damage in EPCs. In addition, relative expression levels of von Willebrand Factor, β-TG, and iNOS and serum concentrations of PAC-1, β-TG, and iNOS were inhibited.

Sodium ferulate can treat AAV by inhibiting NET release and platelet activation and reducing endothelial cell damage.

The continuous emergence of multidrug-resistant (MDR) Acinetobacter baumannii (Ab) strains poses further challenges in its control and clinical management. It is necessary to decipher the mechanisms underlying the high mortality of Ab infections to explore unconventional strategies for controlling outbreaks of drug-resistant infections.

The immune responses of Ab sepsis infection were investigated using flow cytometry, RNA-seq, qRT-PCR, and ELISA and scRNA-seq. The detailed pathways mediating Ab immune responses were also depicted and a specific therapy was developed based on the understanding of the mechanisms underlying Ab-induced cytokine storms.

The results highlighted the critical role of alveolar and interstitial macrophages as targets of Ab during the infection process. These cells were found to undergo polarization towards the M1 phenotype, triggering a cytokine storm that eventually caused the death of the host. The polarization and excessive inflammatory response mediated by macrophages were mainly regulated by the TLR2/Myd88/NF-κB signaling pathway. Suppression of Ab-triggered inflammatory responses and M1 polarization by the drug naproxen (NPXS) was shown to confer full protection of mice from lethal infections.

The findings in this work depict the major mechanisms underlying the high mortality rate of Ab infections and highlight the clinical potential application of anti-inflammatory drugs or immunosuppressants in reducing the mortality of such infections, including those caused by MDR strains.

Funding sources are described in the acknowledgments section.

Pneumocystis jirovecii pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for cancer or solid organ transplants. Severe PjP triggers excessive lung inflammation, resulting in lung function decline and consequential alveolar damage, potentially culminating in acute respiratory distress syndrome. Non-HIV patients face a 30%-60% mortality rate, emphasizing the need for a deeper understanding of inflammatory responses in PjP. Prior research emphasized macrophages in Pneumocystis infections, neglecting neutrophils' role in tissue damage. Consequently, the overemphasis on macrophages led to an incomplete understanding of the role of neutrophils and inflammatory responses. In the current investigation, our RNAseq studies on a murine surrogate model of PjP revealed heightened activation of the NLRP3 inflammasome and NETosis cell death pathways in their lungs. Immunofluorescence staining confirmed neutrophil extracellular trap (NET) presence in the lungs of the P. murina-infected mice, validating our findings. Moreover, isolated neutrophils exhibited NETosis when directly stimulated with P. murina. Isolated NETs compromised P. murina viability in vitro, highlighting the potential role of neutrophils in controlling fungal growth and promoting inflammation during P. murina pneumonia through NLRP3 inflammasome assembly and NETosis. These pathways, essential for inflammation and pathogen elimination, bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation. This pioneering study is the first to identify the formation of NETs and inflammasomes during Pneumocystis infection, paving the way for comprehensive investigations into treatments aimed at mitigating lung damage and augmenting survival rates for individuals with PjP.IMPORTANCEPneumocystis jirovecii pneumonia (PjP) affects individuals with weakened immunity, such as HIV/AIDS, cancer, and organ transplant patients. Severe PjP triggers lung inflammation, impairing function and potentially causing acute respiratory distress syndrome. Non-HIV individuals face a 30%-60% mortality rate, underscoring the need for deeper insight into PjP's inflammatory responses. Past research focused on macrophages in managing Pneumocystis infection and its inflammation, while the role of neutrophils was generally overlooked. In contrast, our findings in P. murina-infected mouse lungs showed neutrophil involvement during inflammation and increased expression of NLRP3 inflammasome and NETosis pathways. Detection of neutrophil extracellular traps further indicated their involvement in the inflammatory process. Although beneficial in combating infection, unregulated neutrophil activation poses a potential threat to lung tissues. Understanding the behavior of neutrophils in Pneumocystis infections is crucial for controlling detrimental reactions and formulating treatments to reduce lung damage, ultimately improving the survival rates of individuals with PjP.

Neutrophil extracellular traps (NETs) are extracellular fibers composed of deoxyribonucleic acid (DNA) and decorated proteins produced by neutrophils. Recently, NETs have been associated with the development of many diseases, including tumors. Herein, we reviewed the correlation between NETs and tumors. In addition, we detailed active compounds from traditional herbal medicine formulations that inhibit NETs, related nanodrug delivery systems, and antibodies that serve as "guiding moieties" to ensure targeted delivery to NETs. Furthermore, we discussed the strategies used by pathogenic microorganisms to evade NETs.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer associated with an immunosuppressive environment. Neutrophil extracellular traps (NETs) were initially described in the context of infection but have more recently been implicated in contributing to the tolerogenic immune response in PDAC. Thus, NETs are an attractive target for new therapeutic strategies. Group A Streptococcus (GAS) has developed defensive strategies to inhibit NETs.

In the present work, we propose utilizing intra-tumoral GAS injection to stimulate anti-tumor activity by inhibiting cancer-promoting NETs. Mice harboring Panc02 or KPC subcutaneous tumors injected with three different M-type GAS strains. Tumors and spleens were harvested at the endpoint of the experiments to assess bacterial colonization and systemic spread, while sera were analyzed for humoral responses toward the streptococcal antigens, especially the M1 and Scl1 proteins. Role of the streptococcal collagen-like protein 1 (Scl1) in anti-PDAC activity was assessed in vivo after intratumoral injection with M1 GAS wild-type, an isogenic mutant strain devoid of Scl1, or a complemented mutant strain with restored scl1 expression. In addition, recombinant Scl1 proteins were tested for NET inhibition using in vitro and ex vivo assays assessing NET production and myeloperoxidase activity.

Injection of three different M-type GAS strains reduced subcutaneous pancreatic tumor volume compared to control in two different murine PDAC models. Limitation of tumor growth was dependent on Scl1, as isogenic mutant strain devoid of Scl1 did not reduce tumor size. We further show that Scl1 plays a role in localizing GAS to the tumor site, thereby limiting the systemic spread of bacteria and off-target effects. While mice did elicit a humoral immune response to GAS antigens, tested sera were weakly immunogenic toward Scl1 antigen following intra-tumoral treatment with Scl1-expressing GAS. M1 GAS inhibited NET formation when co-cultured with neutrophils while Scl1-devoid mutant strain did not. Recombinant Scl1 protein inhibited NETs ex vivo in a dose-dependent manner by suppressing myeloperoxidase activity.

Altogether, we demonstrate that intra-tumoral GAS injections reduce PDAC growth, which is facilitated by Scl1, in part through inhibition of cancer promoting NETs. This work offers a novel strategy by which NETs can be targeted through Scl1 protein and potentiates its use as a cancer therapeutic.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer associated with an immunosuppressive environment. Neutrophil extracellular traps (NETs) were initially described in the context of infection but have more recently been implicated in contributing to the tolerogenic immune response in PDAC. Thus, NETs are an attractive target for new therapeutic strategies. Group A Streptococcus (GAS) has developed defensive strategies to inhibit NETs. In the present work, we propose utilizing intra-tumoral GAS injection to stimulate anti-tumor activity by inhibiting cancer-promoting NETs. Injection of three different M-type GAS strains reduced subcutaneous pancreatic tumor volume compared to control in two different murine PDAC models. Limitation of tumor growth was dependent on streptococcal collagen-like protein 1 (Scl1), as isogenic mutant strain devoid of Scl1 did not reduce tumor size. We further show that Scl1 plays a role in localizing GAS to the tumor site, thereby limiting the systemic spread of bacteria and off-target effects. While mice did elicit a humoral immune response to GAS antigens, tested sera were negative toward Scl1 antigen following intra-tumoral treatment with Scl1-expressing GAS. M1 GAS inhibited NET formation when co-cultured with neutrophils while Scl1-devoid mutant strain did not. Recombinant Scl1 protein inhibited NETs ex vivo in a dose-dependent manner by suppressing myeloperoxidase activity. Altogether, we demonstrate that intra-tumoral GAS injections reduce PDAC growth, which is facilitated by Scl1, in part through inhibition of cancer promoting NETs. This work offers a novel strategy by which NETs can be targeted through Scl1 protein and potentiates its use as a cancer therapeutic.

This study investigates the potential mechanism of moxibustion in the treatment of rheumatoid arthritis (RA) by regulating the neutrophil extracellular trap (NET)/NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome axis with the use of a rat model with adjuvant arthritis (AA).

Four groups, including normal control (NC), AA, moxibustion (MOX), and chlor-amidine (Cl-amidine) were created from 24 Wistar male rats (6 rats/group). After the intervention and treatment respectively, the joint swelling degree (JSD) and arthritis index (AI) were compared. The pathological changes of synovium were observed with hematoxylin and eosin staining and transmission electron microscopy. The formation of NETs in synovial tissues was detected with immunofluorescence staining. The protein expression of myeloperoxidase (MPO), neutrophil elastase (NE), citrullinated histone (Cit-H3), acyl arginine deiminase 4 (PAD-4), and NLRP3 was measured in the synovium of rat ankle joints with western blotting, and the levels of anti-cyclic citrullinated peptide antibody (CCP-Ab) and interleukin (IL)-1β were examined in rat serum with ELISA.

AA modeling markedly increased JSD, AI, synovial protein expression of MPO, NE, Cit-H3, PAD-4, and NLRP3, and serum levels of CCP-Ab and IL-1β in rats (P < 0.01). JSD and AI, as well as the levels of MPO, NE, Cit-H3, PAD-4, NLRP3, CCP-Ab, and IL-1β, were significantly lowered in AA rats by MOX and Cl-amidine (P < 0.01). In addition, AA modeling caused severe pathological injury in the synovium of rats, which was annulled by MOX and Cl-amidine. The formation of NETs in synovium was substantially promoted in rats by AA modeling and was significantly reduced in AA rats after the treatment.

Moxibustion can markedly alleviate synovitis and repress inflammatory factor release in AA rats, which may be achieved by diminished synthesis of NETs or their constituents and the blocked formation of NLRP3 inflammasome.

Toxoplasma gondii, responsible for causing toxoplasmosis, is a prevalent food and waterborne pathogen worldwide. It commonly infects warm-blooded animals and affects more than a third of the global human population. Once ingested, the parasite enters the host's small intestine and rapidly disseminates throughout the body via the bloodstream, infiltrating various tissues. Leukocyte-driven responses are vital against T. gondii, with neutrophils playing a dual role: swiftly recruited to infection sites, releasing inflammatory mediators, and serving as a replication hub and Trojan horses, aiding parasite spread. Neutrophils from various hosts release extracellular traps (NETs) against the protozoan. However, gaps persist regarding the mechanisms of NETs production to parasite and their significance in infection control. This study investigates the interplay between human neutrophils and T. gondii, exploring dynamics, key molecules, and signaling pathways involved in NETs production upon protozoan challenge.

Using confocal and electron microscopy, live cell imaging, pharmacological inhibitors, and DNA quantification assays, we find that human neutrophils promptly release both classical and rapid NETs upon pathogen stimulation. The NETs structure exhibits diverse phenotypes over time and is consistently associated with microorganisms. Mechanisms involve neutrophil elastase and peptidylarginine deiminase, along with intracellular calcium signaling and the PI3K pathway. Unexpectedly, human traps do not diminish viability or infectivity, but potentially aid in capturing parasites for subsequent neutrophil phagocytosis and elimination.

By revealing NETs formation mechanisms and their nuanced impact on T. gondii infection dynamics, our findings contribute to broader insights into host-pathogen relationships.

Neutrophil extracellular traps (NETs) are networks of DNA and various microbicidal proteins released to kill invading microorganisms and prevent their dissemination. However, a NETs excess is detrimental to the host and involved in the pathogenesis of various inflammatory and immunothrombotic diseases. Clostridium perfringens is a widely distributed pathogen associated with several animal and human diseases, that produces many exotoxins, including the phospholipase C (CpPLC), the main virulence factor in gas gangrene. During this disease, CpPLC generates the formation of neutrophil/platelet aggregates within the vasculature, favoring an anaerobic environment for C. perfringens growth. This work demonstrates that CpPLC induces NETosis in human neutrophils. Antibodies against CpPLC completely abrogate the NETosis-inducing activity of recombinant CpPLC and C. perfringens secretome. CpPLC induces suicidal NETosis through a mechanism that requires calcium release from inositol trisphosphate receptor (IP3) sensitive stores, activation of protein kinase C (PKC), and the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathways, as well as the production of reactive oxygen species (ROS) by the metabolism of arachidonic acid. Proteomic analysis of the C. perfringens secretome identified 40 proteins, including a DNAse and two 5´-nucleotidases homologous to virulence factors that could be relevant in evading NETs. We suggested that in gas gangrene this pathogen benefits from having access to the metabolic resources of the tissue injured by a dysregulated intravascular NETosis and then escapes and spreads to deeper tissues. Understanding the role of NETs in gas gangrene could help develop novel therapeutic strategies to reduce mortality, improve muscle regeneration, and prevent deleterious patient outcomes.

Neutrophil extracellular traps (NETs) are large DNA reticular structures secreted by neutrophils and decorated with histones and antimicrobial proteins. As a key mechanism for neutrophils to resist microbial invasion, NETs play an important role in the killing of microorganisms (bacteria, fungi, and viruses). Although NETs are mostly known for mediating microbial killing, increasing evidence suggests that excessive NETs induced by stimulation of physical and chemical components, microorganisms, and pathological factors can exacerbate inflammation and organ damage. This review summarizes the induction and role of NETs in inflammation and focuses on the strategies of inhibiting NETosis and the mechanisms involved in pathogen evasion of NETs. Furthermore, herbal medicine inhibitors and nanodelivery strategies improve the efficiency of inhibition of excessive levels of NETs.

Decondensation and the subsequent release of chromatin from specific immune cells in response to inflammatory stimuli is a highly conserved aspect of the innate immune system and leads to the formation of extracellular traps, observable in nearly all forms of multicellular life. This process is known as ETosis, with the release of DNA and its associated antimicrobial proteins physically capturing and neutralizing pathogens following an infection or tissue damage. Despite the universality of this response, data concerning extracellular traps in non-model organisms is limited, with most invertebrate studies doing little more than proving their existence due to difficulties in stimulation and high interindividual variability in trap production. This study provides a novel, simple, and inexpensive method for the consistent stimulation of extracellular traps in eastern oyster (Crassostrea virginica) hemocytes. Using the methods described in this study, we compared how ploidy impacts the rate, size, and efficacy of extracellular traps. Findings demonstrated that hemocyte extracellular traps were potent antimicrobials against both Gram-positive and Gram-negative bacteria. Furthermore, we provide evidence to suggest that agranulocytes may be the primary ETosis effector cells in C. virginica. This study is the first to describe extracellular traps in C. virginica and highlights the possible benefits of using triploid animals to gain a further understanding of ETosis and the factors that regulate its induction and efficacy.

Mycoplasmas, the smallest known self-replicating organisms, possess a simple structure, lack a cell wall, and have limited metabolic pathways. They are responsible for causing acute or chronic infections in humans and animals, with a significant number of species exhibiting pathogenicity. Although the innate and adaptive immune responses can effectively combat this pathogen, mycoplasmas are capable of persisting in the host, indicating that the immune system fails to eliminate them completely. Recent studies have shed light on the intricate and sophisticated defense mechanisms developed by mycoplasmas during their long-term co-evolution with the host. These evasion strategies encompass various tactics, including invasion, biofilm formation, and modulation of immune responses, such as inhibition of immune cell activity, suppression of immune cell function, and resistance against immune molecules. Additionally, antigen variation and molecular mimicry are also crucial immune evasion strategies. This review comprehensively summarizes the evasion mechanisms employed by mycoplasmas, providing valuable insights into the pathogenesis of mycoplasma infections.

Pancreatic cancer is a highly aggressive form of cancer with a five-year survival rate of only ten percent. Pancreatic ductal adenocarcinoma (PDAC) accounts for ninety percent of those cases. PDAC is associated with a dense stroma that confers resistance to current treatment modalities. Increasing resistance to cancer treatments poses a challenge and a need for alternative therapies. Bacterial mediated cancer therapies were proposed in the late 1800s by Dr. William Coley when he injected osteosarcoma patients with live streptococci or a fabrication of heat-killed Streptococcus pyogenes and Serratia marcescens known as Coley's toxin. Since then, several bacteria have gained recognition for possible roles in potentiating treatment response, enhancing anti-tumor immunity, and alleviating adverse effects to standard treatment options. This review highlights key bacterial mechanisms and structures that promote anti-tumor immunity, challenges and risks associated with bacterial mediated cancer therapies, and applications and opportunities for use in PDAC management.

Mycobacterium tuberculosis complex causes tuberculosis (TB), a disease that causes pulmonary inflammation but can also affect other tissues. Despite macrophages having a defined role in TB immunopathogenesis, other innate immune cells, such as neutrophils, are involved in this process. These cells have high phagocytic ability and a microbial-killing machine comprised of enzymes, antimicrobial peptides, and reactive oxygen species. In the last two decades, a new neutrophil immune response, the neutrophil extracellular traps (NETs), has been intensely researched. NETs comprise DNA associated with histones, enzymes, and antimicrobial peptides. These structures are related to antimicrobial immune response and some immuno-pathogenesis mechanisms. This mini review highlights the role of NETs in tuberculosis and how they can be helpful as a diagnostic tool and/or therapeutic target.

The number of orthopedic implants for bone fixation and joint arthroplasty has been steadily increasing over the past few years. However, implant-associated infection (IAI), a major complication in orthopedic surgery, impacts the quality of life and causes a substantial economic burden on patients and societies. While research and study on IAI have received increasing attention in recent years, the failure rate of IAI has still not decreased significantly. This is related to microbial biofilms and their inherent antibiotic resistance, as well as the various mechanisms by which bacteria evade host immunity, resulting in difficulties in diagnosing and treating IAIs. Hence, a better understanding of the complex interactions between biofilms, implants, and host immunity is necessary to develop new strategies for preventing and controlling these infections. This review first discusses the challenges in diagnosing and treating IAI, followed by an extensive review of the direct effects of orthopedic implants, host immune function, pathogenic bacteria, and biofilms. Finally, several promising preventive or therapeutic alternatives are presented, with the hope of mitigating or eliminating the threat of antibiotic resistance and refractory biofilms in IAI.

Bronchiectasis is a heterogenous disease with multiple aetiologies resulting in inflammation and dilatation of the airways with associated mucus production and chronic respiratory infection. The condition is being recognised ever more frequently as the availability of computed tomography increases. It is associated with significant morbidity and healthcare-related costs. With new understanding of the disease process, varying endotypes, identification of underlying causes and treatable traits, the management of bronchiectasis can be increasingly personalised.

The antioxidant effects of selenium as a component of selenoproteins has been thought to modulate host immunity and viral pathogenesis. Accordingly, the association of low dietary selenium status with inflammatory and immunodeficiency has been reported in the literature; however, the causal role of selenium deficiency in chronic inflammatory diseases and viral infection is still undefined. The COVID-19, characterized by acute respiratory syndrome and caused by the novel coronavirus 2, SARS-CoV-2, has infected millions of individuals worldwide since late 2019. The severity and mortality from COVID-19 have been associated with several factor, including age, sex and selenium deficiency. However, available data on selenium status and COVID-19 are limited, and a possible causative role for selenium deficiency in COVID-19 severity has yet to be fully addressed. In this context, we review the relationship between selenium, selenoproteins, COVID-19, immune and inflammatory responses, viral infection, and aging. Regardless of the role of selenium in immune and inflammatory responses, we emphasize that selenium supplementation should be indicated after a selenium deficiency be detected, particularly, in view of the critical role played by selenoproteins in human health. In addition, the levels of selenium should be monitored after the start of supplementation and discontinued as soon as normal levels are reached. Periodic assessment of selenium levels after supplementation is a critical issue to avoid over production of toxic metabolites of selenide because under normal conditions, selenoproteins attain saturated expression levels that limits their potential deleterious metabolic effects.

During tissue damage caused by infection or sterile inflammation, not only damage-associated molecular patterns (DAMPs), but also resolution-associated molecular patterns (RAMPs) can be activated. These dying cell-associated factors stimulate immune cells localized in the tissue environment and induce the production of inflammatory mediators or specialized proresolving mediators (SPMs). Within the current prospect of science, apoptotic cell death is considered the main initiator of resolution. However, more RAMPs are likely to be released during necrotic cell death than during apoptosis, similar to what has been observed for DAMPs. The inflammatory potential of many regulated forms of necrotic cell death modalities, such as pyroptosis, necroptosis, ferroptosis, netosis, and parthanatos, have been widely studied in necroinflammation, but their possible role in resolution is less considered. In this review, we aim to summarize the relationship between necrotic cell death and resolution, as well as present the current available data regarding the involvement of certain forms of regulated necrotic cell death in necroresolution.

Neutrophil extracellular traps (NETs) are fiber structures composed of chromatin and granular proteins that capture and eliminate microorganisms. The NETs formation is induced in response to pathogens and physiological stimuli; however, some pathogens have developed strategies to evade NETs activity. Trichinella spiralis excretory-secretory (ES) antigens are proteins that allow the establishment of the parasite in the host, facilitating penetration, migration, nutrition, and survival. In this paper we described that ES antigens inhibit NETs release, since neutrophils incubated with these antigens maintains a delobulated nucleus, without the release fibers structures indicative of NETs. We also found that other antimicrobial functions of neutrophils, such as phagocytic activity, degranulation, and ROS production, remain unchanged after incubation with ES antigens. This is relevant since it could constitute a novel strategy for the treatment of autoimmune pathologies in which the formation of NETs performs an important role.

The spread of biofilms on medical implants represents one of the principal triggers of persistent and chronic infections in clinical settings, and it has been the subject of many studies in the past few years, with most of them focused on prosthetic joint infections. We review here recent works on biofilm formation and microbial colonization on a large variety of indwelling devices, ranging from heart valves and pacemakers to urological and breast implants and from biliary stents and endoscopic tubes to contact lenses and neurosurgical implants. We focus on bacterial abundance and distribution across different devices and body sites and on the role of environmental features, such as the presence of fluid flow and properties of the implant surface, as well as on the interplay between bacterial colonization and the response of the human immune system.

Burn injuries elicit a unique and dynamic stress response which can lead to burn injury progression. Though neutrophils represent crucial players in the burn-induced immunological events, the dynamic secretion pattern and systemic levels of neutrophil-derived factors have not been investigated in detail so far. Serum levels of neutrophil elastase (NE), myeloperoxidase (MPO), citrullinated histone H3 (CitH3), and complement factor C3a were quantified in burn victims over 4 weeks post injury. Furthermore, the potential association with mortality, degree of burn injury, and inhalation trauma was evaluated. In addition, leukocyte, platelet, neutrophil, and lymphocyte counts were assessed. Lastly, we analyzed the association of neutrophil-derived factors with clinical severity scoring systems. Serum levels of NE, MPO, CitH3, and C3a were remarkably elevated in burn victims compared to healthy controls. Leukocyte and neutrophil counts were significantly increased on admission day and day 1, while relative lymphocytes were decreased in the first 7 days post burn trauma. Though neutrophil-derived factors did not predict mortality, patients suffering from 3rd degree burn injuries displayed increased CitH3 and NE levels. Accordingly, CitH3 and NE were elevated in cases with higher abbreviated burn severity indices (ABSI). Taken together, our data suggest a role for neutrophil activation and NETosis in burn injuries and burn injury progression. Targeting exacerbated neutrophil activation might represent a new therapeutic option for severe cases of burn injury.

Extracellular DNA (eDNA) is a macromolecule copiously found in various natural microenvironments, but its origin and significance still remain partly mysterious phenomena. Here, the multifaceted origins of eDNA in bacterial biofilms are explored. The release of eDNA can follow a suicidal programmed bacterial apoptosis or a fratricide-induced death, under the control of quorum sensing systems or triggered by specific stressors. eDNA can be released into the extracellular space or as a free macromolecule or enclosed within membrane vesicles or even through an explosion of bubbles. eDNA can also be derived from host tissue cells through bacterial cytolytic/proapoptotic toxins or stolen from neutrophil extracellular traps (NETs). eDNA can alternatively be produced by lysis-independent mechanisms. Sub-inhibitory doses of antibiotics, by killing a fraction of bacteria, result in stimulating the release of eDNA. Even phages appear to play a role in favoring eDNA release. Unveiling the origins of eDNA is critical to correctly address biofilm-associated infections.