Search Results (6)

Background/Objectives: AllergoOncology is a new field of study that investigates the relationship between allergic inflammation and cancer. Mast cells and eosinophils are two critical players in allergy reactions, where they can interact and release bioactive granules. The electron microscope is an indispensable tool for analyzing membrane contacts and degranulation patterns in mast cells and eosinophils. The aim of the present ultrastructural study is to analyze the interactions between tumor-associated eosinophils and mast cells (TATEM) in nine cases of gastric cancer. Methods: Seventy-two gastric cancer samples were analyzed using light microscopy, and nine cases exhibiting TATEM were selected for additional examination by transmission electron microscopy. Results: In seven cases, there was direct interaction between non-activated eosinophils and mast cells demonstrating piecemeal degranulation and/or exocytosis. In cases 8 and 9, both cell types showed more advanced stages of degranulation. Mast cells exhibited either massive degranulation (anaphylactic type) or signs of recovery, while eosinophils displayed cytolysis, with or without extracellular trap formation (ETosis). The concurrent activation of both cell types may indicate a collaborative immune response that could affect tumor behavior. There was a trend toward an association with low-stage (I-II) gastric cancer in patients with TATEM, but this difference was not statistically significant (p = 0.06). Conclusions: This work is the first investigation to present ultrastructural evidence of the intimate relationship between degranulating mast cells and cytolytic eosinophils, with or without ETosis, in gastric cancer. These findings support the emerging field of AllergoOncology, which examines the role of allergy-like immune responses in tumor immunity. Full article

Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates μ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express μ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca²⁺]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca²⁺]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of μ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between μ-opioid and TLR4 receptors. Full article

Over 10 million people worldwide live with Parkinson’s disease (PD) and 4% of affected people are diagnosed before the age of 50. Research on early PD-related pathways is therefore of considerable importance. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that, through post-translational deimination of arginine to citrulline, contribute to changes in protein function, including in pathological processes. Recent studies have highlighted roles for PADs in a range of neurological disorders including PD, but overall, investigations on PADs in Lewy body disease (LBD), including PD, are still scarce. Hence, the current pilot study aimed at performing an immunohistochemistry screen of post-mortem human brain sections from Braak stages 4-6 from PD patients, as well as patients with incidental LBD (ILBD). We assessed differences in PAD isozyme detection (assessing all five PADs), in total protein deimination/citrullination and histone H3 deimination—which is an indicator of epigenetic changes and extracellular trap formation (ETosis), which can elicit immune responses and has involvement in pathogenic conditions. The findings of our pilot study indicate that PADs and deimination are increased in cingulate cortex and hippocampus, particularly in earlier stages of the disease. PAD2 and PAD3 were the most strongly upregulated PAD isozymes, with some elevation also observed for PAD1, while PAD4 and PAD6 increase was less marked in PD brains. Total protein deimination and histone H3 deimination were furthermore increased in PD brains, with a considerable increase at earlier Braak stages, compared with controls. Our findings point to a significant contribution of PADs, which may further aid early disease biomarker discovery, in PD and other LBDs. Full article

Ticks are hematophagous ectoparasites that infest a diverse number of vertebrate hosts. The tick immunobiology plays a significant role in establishing and transmitting many pathogens to their hosts. To control tick infestations, the acaricide application is a commonly used method with severe environmental consequences and the selection of tick-resistant populations. With these drawbacks, new tick control methods need to be developed, and the immune system of ticks contains a plethora of potential candidates for vaccine design. Additionally, tick immunity is based on an orchestrated action of humoral and cellular immune responses. Therefore, the actors of these responses are the object of our study in this review since they are new targets in anti-tick vaccine design. We present their role in the immune response that positions them as feasible targets that can be blocked, inhibited, interfered with, and overexpressed, and then elucidate a new method to control tick infestations through the development of vaccines. We also propose Extracellular Traps Formation (ETosis) in ticks as a process to eliminate their natural enemies and those pathogens they transmit (vectorial capacity), which results attractive since they are a source of acting molecules with potential use as vaccines. Full article

Leukocytes play a major role in combating infections either by phagocytosis, release of antimicrobial granules, or extracellular trap (ET) formation. ET formation is preceded by a certain leukocyte cell death form, known as ETosis, an evolutionarily conserved mechanism of the innate immune system also observed in marine mammals. Besides several biomolecules and microbial stimuli, marine mammal ETosis is also trigged by various terrestrial protozoa and metazoa, considered nowadays as neozoan parasites, which are circulating in oceans worldwide and causing critical emerging marine diseases. Recent studies demonstrated that pinniped- and cetacean-derived polymorphonuclear neutrophils (PMNs) and monocytes are able to form different phenotypes of ET structures composed of nuclear DNA, histones, and cytoplasmic peptides/proteases against terrestrial apicomplexan parasites, e.g., Toxoplasma gondii and Neospora caninum. Detailed molecular analyses and functional studies proved that marine mammal PMNs and monocytes cast ETs in a similar way as terrestrial mammals, entrapping and immobilizing T. gondii and N. caninum tachyzoites. Pinniped- and cetacean leukocytes induce vital and suicidal ETosis, with highly reliant actions of nicotinamide adenine dinucleotide phosphate oxidase (NOX), generation of reactive oxygen species (ROS), and combined mechanisms of myeloperoxidase (MPO), neutrophil elastase (NE), and DNA citrullination via peptidylarginine deiminase IV (PAD4).This scoping review intends to summarize the knowledge on emerging protozoans in the marine environment and secondly to review limited data about ETosis mechanisms in marine mammalian species. Full article

Extracellular traps (ETs) are reticulate structures of extracellular DNA associated with antimicrobial molecules. Their formation by phagocytes (mainly by neutrophils: NETs) has been identified as an essential element of vertebrate innate immune defense. However, as ETs are also toxic to host cells and potent triggers of autoimmunity, their role between pathogen defense and human pathogenesis is ambiguous, and they contribute to a variety of acute and chronic inflammatory diseases. Since the discovery of ET formation (ETosis) a decade ago, evidence has accumulated that most reaction cascades leading to ET release involve ROS. An important new facet was added when it became apparent that ETosis might be directly linked to, or be a variant of, the autophagy cell death pathway. The present review analyzes the evidence to date on the interplay between ROS, autophagy and ETosis, and highlights and discusses several further aspects of the ROS-ET relationship that are incompletely understood. These aspects include the role of NADPH oxidase-derived ROS, the molecular requirements of NADPH oxidase-dependent ETosis, the roles of NADPH oxidase subtypes, extracellular ROS and of ROS from sources other than NADPH oxidase, and the present evidence for ROS-independent ETosis. We conclude that ROS interact with ETosis in a multidimensional manner, with influence on whether ETosis shows beneficial or detrimental effects. Full article