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OBJECTIVE: Aripiprazole is a relatively new atypical antipsychotic agent that has been successfully employed in therapy for schizophrenia and schizoaffective disorders. A few neuroleptics have been used in therapy for patients with borderline personality disorder, which is associated with severe psychopathological symptoms. Aripiprazole, however, has not yet been tested for this disorder, and the goal of this study was to determine whether aripiprazole is effective in the treatment of several domains of symptoms of borderline personality disorder. METHOD: Subjects meeting criteria for the Structured Clinical Interview for DSM-III-R Personality Disorders for borderline personality disorder (43 women and 9 men) were randomly assigned in a 1:1 ratio to 15 mg/day of aripiprazole (N=26) or placebo (N=26) for 8 weeks. Primary outcome measures were changes in scores on the symptom checklist (SCL-90-R), the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), and the State-Trait Anger Expression Inventory and were assessed weekly. Side effects and self-injury were assessed with a nonvalidated questionnaire. RESULTS: According to the intent-to-treat principle, significant changes in scores on most scales of the SCL-90-R, the HAM-D, the HAM-A, and all scales of the State-Trait Anger Expression Inventory were observed in the subjects treated with aripiprazole after 8 weeks. Self-injury occurred in the groups. The reported side effects were headache, insomnia, nausea, numbness, constipation, and anxiety. CONCLUSIONS: Aripiprazole appears to be a safe and effective agent in the treatment of patients with borderline personality disorder. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a de facto innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli. Isolated monocytes were stimulated with SLE-typical nuclear antigens, neutrophil extracellular traps (NETs), and apoptotic microparticles (MPs) or plasma from SLE patients. After five days of rest, cells were restimulated with Toll-like receptor (TLR) agonists, and cytokine production was measured using ELISA. Functional, transcriptomic and epigenetic changes in monocytes from SLE patients were evaluated by ex vivo stimulations, flow cytometric analysis, RNA sequencing, and chromatin immunoprecipitation (ChIP) sequencing for histone 3 lysine 4 trimethylation. We found that in vitro, both MPs and NETs, as well as plasma from SLE patients, can induce trained immunity. Furthermore, circulating monocytes from SLE patients produce increased levels of pro-inflammatory cytokines after stimulation with TLR ligands, indicating trained immunity. This is accompanied by deregulation in histone 3 lysine 4 trimethylation and increased expression of metabolism and inflammation-related genes. Our findings demonstrate that trained immunity can develop against nuclear antigens and that trained immunity is involved in the immunological dysregulation in SLE patients., Competing Interests: Declaration of interests The authors have no conflicting interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recent landmark trials showed that colchicine provides a substantial benefit in reducing major cardiovascular events in patients with coronary artery disease. Yet, its exact mechanism of action is still poorly understood. This study aimed to unravel the effect of colchicine on monocyte and neutrophil phenotype and function. A randomized double-blind placebo-controlled cross-over intervention study was executed in patients with a history of myocardial infarction. In neutrophils, colchicine treatment decreased CD62L expression and NGAL release upon ex vivo stimulation and increased PMA-induced ROS production. The effects of colchicine on monocytes were limited to a decrease in HLA-DR expression in the intermediate and nonclassical monocytes. Also, on the level of RNA expression, colchicine did not affect monocyte phenotype, while affecting various immunomodulating genes in neutrophils. Overall, our study suggests that treatment with colchicine affects neutrophil function, particularly by reducing neutrophil recruitment, lowering concentrations of NGAL, and changing the expression of various genes with immunomodulatory potential, whereas the effect on monocytes is limited., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Regulating innate immunity is an emerging approach to improve cancer immunotherapy. Such regulation requires engaging myeloid cells by delivering immunomodulatory compounds to hematopoietic organs, including the spleen. Here we present a polymersome-based nanocarrier with splenic avidity and propensity for red pulp myeloid cell uptake. We characterized the in vivo behaviour of four chemically identical yet topologically different polymersomes by in vivo positron emission tomography imaging and innovative flow and mass cytometry techniques. Upon intravenous administration, relatively large and spherical polymersomes accumulated rapidly in the spleen and efficiently targeted myeloid cells in the splenic red pulp. When loaded with β-glucan, intravenously administered polymersomes significantly reduced tumour growth in a mouse melanoma model. We initiated our nanotherapeutic's clinical translation with a biodistribution study in non-human primates, which revealed that the platform's splenic avidity is preserved across species., Competing Interests: Competing interests W.J.M.M., L.A.B.J., M.G.N. and Z.A.F. are scientific founders of Trained Therapeutix Discovery. The remaining authors declare no competing interests., (© 2024. The Author(s).)

The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. L. A. B. Joosten is scientific founder of TTxD, LembaTX, and SalvinaTX. M. G. Netea is scientific founder of TTxD and Biotrip. W. J. M. Mulder is scientific founder of TTxD and Biotrip. Other authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes., Competing Interests: Declaration of interests J.O., L.A.B.J., M.G.N., and W.J.M.M. declare that they are scientific founders of Trained Therapeutics Discovery., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Innate immune memory, also called "trained immunity," is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Microparticles (MPs) are small (100 nm - 1 um) extracellular vesicles derived from the plasma membrane of dying or activated cells. MPs are important mediators of intercellular communication, transporting proteins, nucleic acids and lipids from the parent cell to other cells. MPs resemble the state of their parent cells and are easily accessible when released into the blood or urine. MPs also play a role in the pathogenesis of different diseases and are considered as potential biomarkers. MP isolation and characterization is technically challenging and results in different studies are contradictory. Therefore, uniform guidelines to isolate and characterize MPs should be developed. Our understanding of MP biology and how MPs play a role in different pathological mechanisms has greatly advanced in recent years. MPs, especially if derived from apoptotic cells, possess strong immunogenic properties due to the presence of modified proteins and nucleic acids. MPs are often found in patients with autoimmune diseases where MPs for example play a role in the break of immunological tolerance and/or induction of inflammatory conditions. In this review, we describe the main techniques to isolate and characterize MPs, define the characteristics of MPs generated during cell death, illustrate different mechanism of intercellular communication via MPs and summarize the role of MPs in pathological mechanisms with a particular focus on autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rother, Yanginlar, Pieterse, Hilbrands and van der Vlag.)

Neutrophil extracellular traps (NETs) are increasingly recognized to play a role in the pathogenesis of viral infections, including dengue. NETs can be formed NADPH oxidase (NOX)-dependently or NOX-independently. NOX-independent NETs can be induced by activated platelets and are very potent in activating the endothelium. Platelet activation with thrombocytopenia and endothelial dysfunction are prominent features of dengue virus infection. We postulated that dengue infection is associated with NOX-independent NET formation, which is related to platelet activation, endothelial perturbation and increased vascular permeability. Using our specific NET assays, we investigated the time course of NET formation in a cohort of Indonesian dengue patients. We found that plasma levels of NETs were profoundly elevated and that these NETs were predominantly NOX-independent NETs. During early recovery phase (7-13 days from fever onset), total NETs correlated negatively with platelet number and positively with platelet P-selectin expression, the binding of von Willebrand factor to platelets and levels of Syndecan-1. Patients with gall bladder wall thickening, an early marker of plasma leakage, had a higher median level of total NETs. Ex vivo , platelets induced NOX-independent NET formation in a dengue virus non-structural protein 1 (NS1)-dependent manner. We conclude that NOX-independent NET formation is enhanced in dengue, which is most likely mediated by NS1 and activated platelets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Garishah, Rother, Riswari, Alisjahbana, Overheul, van Rij, van der Ven, van der Vlag and de Mast.)

Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell-specific nanobiologics in apolipoprotein E-deficient ( Apoe -/- ) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages' inflammatory activity. By investigating transcriptome modifications, we identified Psap , a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that Psap inhibition suppressed both glycolysis and oxidative phosphorylation. Transplantation of Psap -/- bone marrow to low-density lipoprotein receptor knockout ( Ldlr -/- ) mice led to a reduction in atherosclerosis development and plaque inflammation. Last, we confirmed the relationship between PSAP expression and inflammation in human carotid atherosclerotic plaques. Our findings provide mechanistic insights into the development of atherosclerosis and identify prosaposin as a potential therapeutic target., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Even though tumours are considered to occur frequently in pet hamsters, there is only a small number of scientific reports in current literature., Methods: Pathological reports from 177 hamsters were evaluated., Results: Of these, 78 were male and 75 were female. Median age of affected hamsters was 12 months (range 2-34). Integumental tumours were the most common neoplasms (62%, 109/177). As far as species was known, the number of Syrian hamsters (52%, 30/58) affected by tumours seemed to be lower than the number of affected dwarf hamsters (85%, 47/55). Tumours of the hematopoietic system were the second most frequently neoplasms (17%, 30/177). Relative number of neoplasms of the endocrine system, tumours of the digestive system (1.7%, 3/177) and other tumours (4%, 7/177 each) was low. The majority of integumental tumours were epithelial (66%; 91/126)., Conclusion: This study aimed to analyze data from veterinary surgeries and pathological institutes about the occurrence of spontaneous tumours in Syrian hamsters and dwarf hamsters to give information about the frequency of tumours, prognosis and survival time. This is the first study about tumours in pet hamsters in Germany so far., (© 2021 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

The concept of empathy describes our capacity to understand the emotions and intentions of others and to relate to our conspecifics. Numerous studies investigated empathy as a state as well as a stable personality trait. For example, recent studies in neuroscience suggest, among other brain areas such as the insula or the ACC, a role of the somatosensory cortices for empathy (e.g., when observing someone else being touched). Since the classic understanding of the primary somatosensory cortex is to represent touch on the body surface, we here aimed to test whether tactile performance is linked to the personality trait empathy. To test this, we examined the tactile acuity of 95 healthy participants (mean age 31 years) by using a two-point discrimination threshold task at the index fingers. Trait empathy was assessed by employing the interpersonal reactivity index (IRI), which measures self-reported empathy with four scales (empathic concern, perspective taking, fantasy, and personal distress). Results of regression analyses suggested the subscale empathic concern to be positively associated with performance in the tactile acuity task. We discuss this finding in the light of recent studies on empathy and consider possible implications of tactile training to enhance empathy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schaefer, Joch and Rother.)

Hydroxychloroquine is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed Candida , trained innate immunity can be modeled in vitro . In this model, hydroxychloroquine inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that hydroxychloroquine inhibits trained immunity in vitro , which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. To test this hypothesis, heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n = 10) and COVID-19 patients (n = 48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity was associated with disease severity including the need for intensive care, lactate dehydrogenase levels, and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored., (Copyright © 2020 Buijsers, Yanginlar, de Nooijer, Grondman, Maciej-Hulme, Jonkman, Janssen, Rother, de Graaf, Pickkers, Kox, Joosten, Nijenhuis, Netea, Hilbrands, van de Veerdonk, Duivenvoorden, de Mast and van der Vlag.)

Objectives: Neutrophil extracellular traps (NETs) act in various rheumatic diseases. Although NET formation was originally described as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-dependent pathway, it appears that there are also NOX-independent pathways of NET release. Currently, no tools are available that can discriminate between both NET-forming pathways. We aimed to develop a serological method allowing the discrimination between NETs generated through NOX-dependent or NOX-independent pathways., Methods: Histones from in vitro generated NOX-dependent and NOX-independent NETs were characterised with a panel of lupus-derived antibodies against N-terminal histone tails using immunofluorescence microscopy, western blot and ELISA. NETs in patients with NET-associated diseases, that is, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA) and sepsis, were characterised in sandwich ELISAs employing antibodies against myeloperoxidase (MPO) and N-terminal histone tails as detecting and capturing antibodies, respectively. Functional responses of endothelial cells to NOX-dependent and NOX-independent NETs were assessed as well., Results: Neutrophil elastase cleaves the N-terminal tails of core histones during NOX-dependent, but not during NOX-independent NET formation. Consequently, the detection of MPO-histone complexes with antibodies against N-terminal histone tails allows discrimination between NETs formed through a NOX-dependent or NOX-independent manner. Characterisation of in vivo circulating NETs revealed the presence of NOX-independent NETs in RA, SLE and sepsis, but NOX-dependent NETs in PsA. NOX-independent NETs displayed an increased capacity to activate endothelial cells when compared with NOX-dependent NETs., Conclusions: These results indicate heterogeneity in NET-forming pathways in vivo and highlight the need for disease-specific strategies to prevent NET-mediated pathology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is characterized by IgA depositions in the kidney. Deficiency of CD37, a leukocyte-specific tetraspanin, leads to spontaneous development of renal pathology resembling IgAN. However, the underlying molecular mechanism has not been resolved. Here we found that CD37 expression on B cells of patients with IgAN was significantly decreased compared to B cells of healthy donors. Circulating interleukin (IL)-6 levels, but not tumor necrosis factor-α or IL-10, were elevated in Cd37 -/- mice compared to wild-type mice after lipopolysaccharide treatment. Cd37 -/- mice displayed increased glomerular neutrophil influx, immune complex deposition, and worse renal function. To evaluate the role of IL-6 in the pathogenesis of accelerated renal pathology in Cd37 -/- mice, we generated Cd37xIl6 double-knockout mice. These double-knockout and Il6 -/- mice displayed no glomerular IgA deposition and were protected from exacerbated renal failure following lipopolysaccharide treatment. Moreover, kidneys of Cd37 -/- mice showed more mesangial proliferation, endothelial cell activation, podocyte activation, and segmental podocyte foot process effacement compared to the double-knockout mice, emphasizing that IL-6 mediates renal pathology in Cd37 -/- mice. Thus, our study indicates that CD37 may protect against IgA nephropathy by inhibition of the IL-6 pathway., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Endocytosis of surface receptors and their polarized recycling back to the plasma membrane are central to many cellular processes, such as cell migration, cytokinesis, basolateral polarity of epithelial cells and T cell activation. Little is known about the mechanisms that control the organization of recycling endosomes and how they connect to receptor endocytosis. Here, we follow the endocytic journey of the T cell receptor (TCR), from internalization at the plasma membrane to recycling back to the immunological synapse. We show that TCR triggering leads to its rapid uptake through a clathrin-independent pathway. Immediately after internalization, TCR is incorporated into a mobile and long-lived endocytic network demarked by the membrane-organizing proteins flotillins. Although flotillins are not required for TCR internalization, they are necessary for its recycling to the immunological synapse. We further show that flotillins are essential for T cell activation, supporting TCR nanoscale organization and signaling.

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Lupus nephritis (LN) is the major cause of morbidity and mortality in patients with SLE. Central to the pathogenesis of SLE is the accumulation of cellular waste, especially apoptotic microparticles (MPs), which stimulates diverse immune reactions including the formation of neutrophil extracellular traps (NETs). In this study, we investigated the content of MPs from SLE patients with and without (active) LN, their capacity to stimulate NET release, and assessed the molecular mechanisms underlying MP-induced NETosis., Methods: MPs from SLE patients with biopsy-proven active LN, remissive LN, without LN, and healthy controls were characterized by flow cytometry. Isolated neutrophils were exposed to MPs derived from either patient plasma or apoptotic human umbilical vein endothelial cells, and NET release was quantified by immunofluorescence imaging, spectrofluorometry or an in-house developed NET ELISA., Results: MPs from SLE patients with active LN contain higher levels of acetylated chromatin compared to MPs from those with remissive LN, without LN, or healthy controls. MPs enriched in hyperacetylated chromatin are more potent in inducing NETosis when compared to MPs containing moderate acetylated chromatin. The release of NETs in response to MPs occurs rapidly in a concentration-dependent manner and proceeds independent from the formation of reactive oxygen species (ROS)., Conclusion: Our data suggest that MPs containing acetylated chromatin drive ROS-independent NET release in SLE patients with active LN, which may lead to the glomerular deposition of NETs and subsequent NET-driven LN.

Objective: An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity., Approach and Results: Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell-cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional β-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition., Conclusions: These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of β-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release., (© 2017 American Heart Association, Inc.)

The release of neutrophil extracellular traps (NETs), either during "suicidal" or "vital" NETosis, represents an important strategy of neutrophils to combat Gram-negative bacteria. Lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, is a reported stimulus for NET formation. Although it is widely acknowledged that the structural diversity in LPS structures can elicit heterogeneous immune responses, species- and serotype-specific differences in the capacity of LPS to trigger NET formation have not yet been investigated. In the present study, we compared the NET-inducing potential of LPS derived from Escherichia coli (serotypes O55:B5, O127:B8, O128:B12, O111:B4 , and O26:B6 ), Salmonella enterica (serotype enteritidis ), and Pseudomonas aeruginosa (serotype 10 ), under platelet-free and platelet-rich conditions in vitro , and in whole blood ex vivo . Here, we demonstrate that under serum- and platelet-free conditions, mimicking tissue circumstances, neutrophils discriminate between LPS of different bacterial sources and selectively release NETs only in response to LPS derived from E. coli O128:B12 and P. aeruginosa 10 , which both induced "suicidal" NETosis in an autophagy- and reactive oxygen species (ROS)-dependent, but TLR4-independent manner. Intriguingly, in whole blood cultures ex vivo , or in vitro in the presence of platelets, all LPS serotypes induced "vital" NET formation. This platelet-dependent release of NETs occurred rapidly without neutrophil cell death and was independent from ROS formation and autophagy but required platelet TLR4 and CD62P-dependent platelet-neutrophil interactions. Taken together, our data reveal a complex interplay between neutrophils and LPS, which can induce both "suicidal" and "vital" NETosis, depending on the bacterial origin of LPS and the presence or absence of platelets. Our findings suggest that LPS sensing by neutrophils may be a critical determinant for restricting NET release to certain Gram-negative bacteria only, which in turn may be crucial for minimizing unnecessary NET-associated immunopathology.

Objective: Circulating chromatin-containing apoptotic material and/or neutrophil extracellular traps (NETs) have been proposed to be an important driving force for the antichromatin autoimmune response in patients with systemic lupus erythematosus (SLE). The aim of this study was to determine the exact nature of microparticles in the circulation of SLE patients and to assess the effects of the microparticles on the immune system., Methods: We analyzed microparticles isolated from the plasma of patients with SLE, rheumatoid arthritis (RA), and systemic sclerosis (SSc), as well as from healthy subjects. The effects of the microparticles on blood-derived dendritic cells (DCs) and neutrophils were assessed by flow cytometry, enzyme-linked immunosorbent assay, and immunofluorescence microscopy., Results: In SLE patients, we identified microparticles that were highly positive for annexin V and apoptosis-modified chromatin that were not present in healthy subjects or in RA or SSc patients. These microparticles were mostly CD31+/CD45- (endothelial), partly CD45+/CD66b+ (granulocyte), and negative for B and T cell markers. Microparticles isolated from the plasma of SLE patients increased the expression of the costimulatory surface molecules CD40, CD80, CD83, and CD86 and the production of proinflammatory cytokines interleukin-6, tumor necrosis factor, and interferon-α by blood-derived plasmacytoid DCs (PDCs) and myeloid DCs (MDCs). SLE microparticles also primed blood-derived neutrophils for NETosis. Microparticles from healthy subjects and from RA or SSc patients exhibited no significant effects on MDCs, PDCs, and NETosis., Conclusion: Circulating microparticles in SLE patients include a population of apoptotic cell-derived microparticles that has proinflammatory effects on PDCs and MDCs and enhances NETosis. These results underline the important role of apoptotic microparticles in driving the autoimmune response in SLE patients., (© 2016, American College of Rheumatology.)

Background: The impact of signal-dependent transcription factors, such as glucocorticoid receptor and nuclear factor kappa-b, on the three-dimensional organization of chromatin remains a topic of discussion. The possible scenarios range from remodeling of higher order chromatin architecture by activated transcription factors to recruitment of activated transcription factors to pre-established long-range interactions., Results: Using circular chromosome conformation capture coupled with next generation sequencing and high-resolution chromatin interaction analysis by paired-end tag sequencing of P300, we observed agonist-induced changes in long-range chromatin interactions, and uncovered interconnected enhancer-enhancer hubs spanning up to one megabase. The vast majority of activated glucocorticoid receptor and nuclear factor kappa-b appeared to join pre-existing P300 enhancer hubs without affecting the chromatin conformation. In contrast, binding of the activated transcription factors to loci with their consensus response elements led to the increased formation of an active epigenetic state of enhancers and a significant increase in long-range interactions within pre-existing enhancer networks. De novo enhancers or ligand-responsive enhancer hubs preferentially interacted with ligand-induced genes., Conclusions: We demonstrate that, at a subset of genomic loci, ligand-mediated induction leads to active enhancer formation and an increase in long-range interactions, facilitating efficient regulation of target genes. Therefore, our data suggest an active role of signal-dependent transcription factors in chromatin and long-range interaction remodeling.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Circulating immune complexes of chromatin and autoantibodies deposit in various tissues leading to inflammation and tissue damage. It has been well documented that autoimmunity in SLE depends on autoreactive T cells. In this review, we summarize the literature that addresses the roles of T cell signaling, and Th17 and regulatory T cells (Tregs) in the development of SLE. T cell receptor (TCR) signaling appears to be aberrant in T cells of patients with SLE. In particular, defects in the TCRζ chain, Syk kinase, and calcium signaling molecules have been associated with SLE, which leads to hyperresponsive autoreactive T cells. Furthermore, in patients with SLE increased numbers of autoreactive Th17 cells have been documented, and Th17 cells appear to be responsible for tissue inflammation and damage. In addition, reduced numbers of Tregs as well as Tregs with an impaired regulatory function have been associated with SLE. The altered balance between the number of Tregs and Th17 cells in SLE may result from changes in the cytokine milieu that favors the development of Th17 cells over Tregs.

Objective: The aim of this study was to examine whether bioenergetic exercises (BE) significantly influence the inpatient psychotherapeutic treatment results for Turkish immigrants with chronic somatoform disorders., Method: In a 6-week randomized, prospective, controlled trial, we treated a sample of 128 Turkish patients: 64 were randomly assigned to BE and 64 participated in gymnastic exercises in lieu of BE. The Symptom Checklist (SCL-90-R) and State-Trait Anger Expression Inventory (STAXI) were employed., Results: According to the intent-to-treat principle, the bioenergetic analysis group achieved significantly better treatment results on most of the SCL-90-R and STAXI scales., Conclusions: BE appears to improve symptoms of somatization, social insecurity, depressiveness, anxiety, and hostility in the inpatient therapy of subjects with chronic somatoform disorders. Reduction of the anger level and reduction in directing anger inwards, with a simultaneous increase of spontaneous outward emotional expression, could be expected.

Objective: This study was carried out to examine sociopsychopathological predictors of prospective observed suicide attempts in bulimic women purging type without comorbid major depression (BNG) at the time of study entry and in woman with major depression without comorbid eating disorder at the time of study entry (MDG)., Methods: Data from 28 BNG (age 23.5 +/- 3.6) and 126 MDG women (age 33.4 +/- 5.1) who had attempted suicide during 12 months' monitoring were compared., Results: A univariate comparison of the two groups revealed various differences. Analysis of risk factors for suicide attempts using stepwise logistic regression was conducted separately for each group. The derived logistic models showed that patients from the BNG group had a history of higher incidence of sexual abuse in childhood, as well as abuse of laxatives and illicit drugs; they also lacked orientation in life, felt lonely despite family and friends, tended to direct their anger outward, and were unable to relax., Conclusions: Sociopsychopathological risk factors for suicide attempts in the BNG and MDG appear to vary.