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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)-induced and neutrophil-related transcripts. Increased production and/or bioav...
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Background:
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Objective:
To evaluate the efficacy and safety of in...
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Citations
... This resulted in the release of NETs. Then, NETs activate plasmacytoid dendritic cells to enhance the uptake and recognition of mammalian DNA, prompting them to produce elevated levels of IFN-α [19]. Another possible trigger of IFN-I production is oxidative DNA damage. ...
The role of type I interferon (IFN-I) signaling in systemic lupus erythematosus (SLE) has been well established. However, unanswered questions remain regarding the applicability of these findings to pediatric-onset SLE. The aim of this review is to provide an overview of the novel discoveries on IFN-I signaling in pediatric-onset SLE.
A literature search was conducted in the PubMed database using the following keywords: “pediatric systemic lupus erythematosus” and “type I interferon”.
IFN-I signaling is increased in pediatric SLE, largely due to the presence of plasmacytoid dendritic cells and pathways such as cyclic GMP-AMP synthase–stimulator of interferon genes–TANK-binding kinase 1 and Toll-like receptor (TLR)4/TLR9. Neutrophil extracellular traps and oxidative DNA damage further stimulate IFN-I production. Genetic variants in IFN-I-related genes, such as IFN-regulatory factor 5 and tyrosine kinase 2, are linked to SLE susceptibility in pediatric patients. In addition, type I interferonopathies, characterized by sustained IFN-I activation, can mimic SLE symptoms and are thus important to distinguish. Studies on interferonopathies also contribute to exploring the pathogenesis of SLE. Measuring IFN-I activation is crucial for SLE diagnosis and stratification. Both IFN-stimulated gene expression and serum IFN-α2 levels are common indicators. Flow cytometry markers such as CD169 and galectin-9 are promising alternatives. Anti-IFN therapies, such as sifalimumab and anifrolumab, show promise in adult patients with SLE, but their efficacy in pediatric patients requires further investigation. Janus kinase inhibitors are another treatment option for severe pediatric SLE patients.
This review presents an overview of the IFN-I pathway in pediatric SLE. Understanding the intricate relationship between IFN-I and pediatric SLE may help to identify potential diagnostic markers and targeted therapies, paving the way for improved patient care and outcomes.
... Neutrophil extracellular traps (NETs) are typically produced and released through a unique process of programmed inflammatory cell death, a specific way in which neutrophils die [62]. SLE NETs activate pDCs and induce IFN-I secretion, which also triggers NETosis in healthy neutrophils [63]. RSAD2 has been demonstrated to be highly expressed and induced in neutrophils in RA [64], acute lymphocytic choriomeningitis virus [65] and asthma [66], and this process is also associated with IFN. ...
Autoimmune diseases are typically characterized by aberrant activation of immune system that leads to excessive inflammatory reactions and tissue damage. Nevertheless, precise targeted and efficient therapies are limited. Thus, studies into novel therapeutic targets for the management of autoimmune diseases are urgently needed. Radical S-adenosyl methionine domain-containing 2 (RSAD2) is an interferon-stimulated gene (ISG) renowned for the antiviral properties of the protein it encodes, named viperin. An increasing number of studies have underscored the new roles of RSAD2/viperin in immunomodulation and mitochondrial metabolism. Previous studies have shown that there is a complex interplay between RSAD2/vipeirn and mitochondria and that binding of the iron-sulfur (Fe-S) cluster is necessary for the involvement of viperin in mitochondrial metabolism. Viperin influences the proliferation and development of immune cells as well as inflammation via different signaling pathways. However, the function of RSAD2/viperin varies in different studies and a comprehensive overview of this emerging theme is lacking. This review will describe the characteristics of RSAD2/viperin, decipher its function in immunometabolic processes, and clarify the crosstalk between RSAD2/viperin and mitochondria. Furthermore, we emphasize the crucial roles of RSAD2 in autoimmune diseases and its potential application value.
... Elevated levels of IL-1β have been observed to activate NETs [98]. The resulting NETs may play a role in AD progression by damaging the BBB and neuronal cells [99,100]. Studies indicate that platelets significantly contribute to the formation of vascular NETs [68,101,102]. ...
Alzheimer’s disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and cerebrovascular dysfunction. The presence of chronic neuroinflammation, breaches in the blood-brain barrier (BBB), and increased levels of inflammatory mediators are central to the pathogenesis of AD. These factors promote the penetration of immune cells into the brain, potentially exacerbating clinical symptoms and neuronal death in AD patients. While microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD, recent evidence suggests the infiltration of cerebral vessels and parenchyma by peripheral immune cells, including neutrophils, T lymphocytes, B lymphocytes, NK cells, and monocytes in AD. These cells participate in the regulation of immunity and inflammation, which is expected to play a huge role in future immunotherapy. Given the crucial role of peripheral immune cells in AD, this article seeks to offer a comprehensive overview of their contributions to neuroinflammation in the disease. Understanding the role of these cells in the neuroinflammatory response is vital for developing new diagnostic markers and therapeutic targets to enhance the diagnosis and treatment of AD patients.
... Another study highlighted the inhibitory role of Dex in preventing NET formation, release of NET-associated DNA and key proteins induced by various stimuli, including phorbol 12myristate 13-acetate (PMA) and LPS(Denny et al. 2010). Neutrophils from SLE patients treated with Dex exhibited a decreased capacity for NET formation, suggesting the potential therapeutic value of Dex in managing NET-associated complications in autoimmune diseasesGarcia-Romo et al. (2011). Our earlier studies in SLE employing Dex or IFN-γ preconditioned MSCs have yielded significant disease ameliorating changes in the inflammatory profiles including reduction in autoantibodies, Th17 cytokines, Th17 cells, double negative T cells, inflammatory neutrophils population, organ pathology, organ physiology, improvement in T and B regulatory cells, and symptoms of alopecia, seizures, and limb inflammation. ...
Background
Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses, with neutrophil extracellular traps (NETs) playing a significant role. NETs are recognized by autoantibodies in SLE patients, exacerbating pathology. Both excessive NET formation and impaired degradation contribute to SLE pathophysiology.
Objective
To investigate the immunomodulatory effects of DW and IW on NETosis and associated protein markers in SLE patients’ LPS or ribonucleoprotein immune complexes (RNP ICs) induced neutrophils and in pristane induced lupus (PIL) model. And to elucidate the mechanism involved therein.
Methods
We investigated the immunomodulatory effects of DW and IW on NETosis in SLE. Utilizing in vitro and in vivo models, we assessed the impact of preconditioned media on NET formation and associated protein markers neutrophil elastase (NE), citrullinated histone (citH3), myeloperoxidase (MPO), cytoplasmic and mitochondrial ROS production. We also examined the involvement of key immunomodulatory factors present in DW and IW, including prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor-beta (TGF-β).
Results
Preconditioned media effectively suppressed NETosis and reduced ROS generation in SLE neutrophils, indicating their immunomodulatory potential. Inhibition studies implicated IDO and PGE2 in mediating this effect. Combined treatment with DW or IW together with hydroxychloroquine (HCQ) demonstrated superior efficacy over HCQ alone, a standard SLE medication. In PIL mouse model, DW and IW treatments reduced NETosis, ROS generation, as evidenced by decreased NET-associated protein expression in vital organs.
Conclusion
Our study highlights the multifaceted impact of IW and DW on NETosis, ROS dynamics, and lupus severity in SLE. These findings underscore the potential of preconditioned media for the development of targeted, personalized approaches for SLE treatment.
... Чрезмерное образование или нарушение клиренса NETs способствуют развитию и поддержанию многих хронических неинфекционных заболеваний, в том числе и аутоиммунных [7]. Известно, что при СКВ NETs являются источниками аутоантигенов [8][9][10], компоненты NETs способны активировать иммуновоспалительные клетки [9,10], систему комплемента [11], индуцировать синтез интерферона α [11][12][13], активировать систему свертывания крови и вызывать дисфункцию эндотелия и повреждение тканей [8,14]. Несмотря на важность исследования ВН, лишь немногие работы сосредоточены на изучении связи между NETs и люпус-нефритом. ...
Aim. To evaluate the levels of MPO-DNA complex in patients with systemic lupus erythematosus (SLE) and its association with the presence of lupus nephritis (LN). Materials and methods. The study included 77 patients with SLE, of whom 30 had SLE without anti phospholipid syndrome (APS), 47 had SLE with APS, and 20 were healthy individuals serving as the control group. The MPO-DNA complex in the serum was investigated using ELISA. Results. The levels of MPO-DNA complex in serum were significantly higher in patients with SLE compared to healthy controls (p=0.001). Among the patients with SLE, 30 (39%) had elevated levels of MPO-DNA complex. The presence of elevated MPO-DNA complex was significantly associated with the presence of a history of LN (p=0.009). Moreover, among the patients included in the study, 20 had active LN, and patients with elevated MPO-DNA complex levels were more likely to have active LN than patients without elevated MPO-DNA complex concentrations [12 (40%) of 30 vs 8 (17%) of 47, χ2=5.029; p=0.034]. An association was found between elevated levels of MPO-DNA complex and the presence of proteinuria, hematuria, cellular hematic/granular casts and aseptic leukocyturia. A direct correlation of MPO-DNA complex with SLEDAI-R was found in patients with active LN (rs=0.497; p=0.026). Conclusion. Elevated levels of MPO-DNA complex were detected in 39% of patients with SLE. These patients had a higher prevalence of LN in their medical history and at the time of inclusion in the study. The correlation between MPO-DNA complex levels and the activity of LN according to SLEDAI-R indicates the potential role of MPO-DNA complex as a biomarker for assessing the activity of renal damage in SLE.
... This suggests that aberrant regulation of NETs is involved in the pathogenesis of DM/PM and may be one of the factors triggering and exacerbating ILD [11]. Also, NETs stimulate plasmacytoid dendritic cells to release type I IFN, which further disrupts the cytokine network [41,42], leading to continuous NET formation. If these excess NETs are not cleared to halt the cycle, they can damage to the lung endothelium and disrupt homeostasis [43]. ...
... Activation of the type I IFN pathway exhibited a positive correlation with disease activity in DM and PM, while type II IFN signatures were found to be upregulated in ASS [54]. NETs can promote the secretion of type I IFN, and in turn, IFN-α can stimulate the formation of NETs [41]. Neutrophils cause myofiber damage both in vitro and in vivo [55], and oxidants released by these cells result in severe cellular damage. ...
Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of chronic autoimmune diseases characterized by muscle damage and extramuscular symptoms, including specific skin rash, arthritis, interstitial lung disease, and cardiac involvement. While the etiology and pathogenesis of IIM are not yet fully understood, emerging evidence suggests that neutrophils and neutrophil extracellular traps (NETs) have a role in the pathogenesis. Recent research has identified increased levels of circulating and tissue neutrophils as well as NETs in patients with IIM; these contribute to the activation of the type I and type II interferons pathway. During active IIM disease, myositis-specific antibodies are associated with the formation and incomplete degradation of NETs, leading to damage in the lungs, muscles, and blood vessels of patients. This review focuses on the pathogenic role and clinical significance of neutrophils and NETs in IIM, and it includes a discussion of potential targeted treatment strategies.
... We focused on the following novel immune cells. First were the activated neutrophils that eject chromatin and granular proteins into the extracellular spaces, forming neutrophil extracellular DNA traps (NETs); this class of neutrophils is known to drive autoimmunity and inflammation (e.g., systemic lupus erythematosus [SLE] [21], and stroke [41]) and to enhance the occurrence of severe organ damage [13]. Second were T cells that express the melanoma cell adhesion molecule (MCAM, CD146), including MCAM + CD4 + helper T (T H ) 17 cells and MCAM + CD8 + cytotoxic T (T C ) 17 cells. ...
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood–brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive ‘stage-dependent’ investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM⁺) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3⁺) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103⁺ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under “standby” conditions in all stages. Furthermore, CD103⁺ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM⁺ TH17/TC17 cells, and CD103⁺ TRM cells, as well as promoting the expansion of FOXP3⁺ Treg cells, may be effective in treating and preventing relapses of NMOSD.
... Кроме того, в отличие от HDNs, у LDNs снижена способность к фагоцитозу и усилена способность к спонтанному высвобождению НВЛ [30]. Помимо повышенной способности к формированию НВЛ, у пациентов с СКВ отмечается нарушение процессов их деградации и элиминации, которое связано с активностью заболевания и уровнем аутоантител [31,32]. Неспособность удалять аутоантигены, такие как ДНК, гистоны, белки гранул, присутствующие в НВЛ, ведет к продолжительной стимуляции иммунных клеток, образованию аутореактивных клеток, аутоантител и гиперкоагуляции. ...
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology characterized by the overproduction of autoantibodies against various components of the nucleus of the patient's own cells with the development of immunoinflammatory tissue damage. In recent years, more and more data have accumulated on the involvement of neutrophils in the development of the clinical symptoms of SLE, and DNA-containing structures and neutrophil extracellular traps (NETs) playing an important role in this process. Effective neutralization of NETs in SLE can be achieved by removing circulating proteins and molecules associated with NETs from the bloodstream by selective plasma sorption of DNA using the NucleoCapture Device.
This article describes the case of a patient who underwent three plasma sorption sessions aiming to suppress the activity of SLE. During the therapy, significant positive dynamics were achieved: the SLEDAI-2K index decreased from 32 to 12 points, the number of leukocytes in the blood normalized, renal function improved, and the immunological activity of the disease decreased.
... Extracellular traps (ETs) serve as a 1 double-edged sword (Malech et al., 2020, as they effectively trap and eradicate various pathogens such as bacteria (Pieper et al., 2017), viruses (Cesta et al., 2023), fungi (He et al., 2022) and parasites while forming a protective barrier for the body. However, abnormal release and degradation of ETs can also lead to immune damage in tissues and organs (Papayannopoulos, 2018, such as pancreatitis (Leppkes et al., 2016), atherosclerosis (Duewell et al., 2010), thrombosis (Brill et al., 2011) , and systemic lupus erythematosus (Garcia-Romo et al., 2011). Our previous studies have demonstrated that GT inhibits HETs to promote tissue damage in ducklings . ...
Gliotoxin (GT) belongs to the epipolythiodioxopiperazine (ETP) family, which is considered a crucial virulence determinant among the secondary metabolites produced by Aspergillus fumigatus. The metabolites are commonly found in food and feed, contributing to the invasion and immune escape of Aspergillus fumigatus, thereby posing a significant threat to the health of livestock, poultry, and humans. Heterophil extracellular traps (HETs), a novel form of innate immune defense, have been documented in the chicken's innate immune systems for capturing and eliminating invading microbes. However, the effects and mechanisms of GT on the production of duck HETs in vitro remain unknown. In this study, we first confirmed the presence of HETs in duck innate immune systems and further investigated the molecular mechanism underlying GT-induced HETs release. Our results demonstrate that GT can trigger typical release of HETs in duck. The structures of GT-induced HETs structures were characterized by DNA decoration, citrullinated histones 3, and elastase. Furthermore, NADPH oxidase, glycolysis, ERK1/2 and p38 signaling pathway were found to regulate GT-induced HETs. In summary, our findings reveal that gliotoxin activates HETs release in the early innate immune system of duck while providing new insights into the immunotoxicity of GT towards ducks.
... When NETs are formed by LDG cells, proteins from these structures are released into the microenvironment, including a variety of proteins such as LL37, αand β-defensins, and high-mobility group box 1 (HMGB1). These proteins bind to DNA and subsequently activate plasmacytoid dendritic cells (pDCs) via Toll-like receptor 9 (TLR9), triggering the synthesis of interferon-alpha (IFN-α) [40,99]. Importantly, IFN-α acts as a potent inducer of NETosis in SLE patients [100], establishing a positive feedback loop that increases the presence of NETs in body fluids. ...
Neutrophil extracellular traps (NETs) are intricate fibrous structures released by neutrophils in response to specific stimuli. These structures are composed of depolymerized chromatin adorned with histones, granule proteins, and cytosolic proteins. NETs are formed via two distinct pathways known as suicidal NETosis, which involves NADPH oxidase (NOX), and vital NETosis, which is independent of NOX. Certain proteins found within NETs exhibit strong cytotoxic effects against both pathogens and nearby host cells. While NETs play a defensive role against pathogens, they can also contribute to tissue damage and worsen inflammation. Despite extensive research on the pathophysiological role of NETs, less attention has been paid to their components, which form a unique structure containing various proteins that have significant implications in a wide range of diseases. This review aims to elucidate the components of NETs and provide an overview of their impact on host defense against invasive pathogens, autoimmune diseases, and cancer.
