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Systemic Lupus Erythematosus
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Vaneet K. Sandhu, Neha V. Chiruvolu, Daniel J. Wallace
Neutrophils have also been of interest as potential triggers in IFN-1 production. This is especially interesting given their involvement in the formation of LE cells. It is still up for debate as to whether neutrophils induce IFN-1 as complete cells or as degradation products. It is known that neutrophils extensively contribute to apoptosis burden owing to their short half-lives. Neutrophil extracellular traps (NETs) are mechanisms through which the body immobilizes and neutralizes pathogens by releasing DNA-peptide complexes (nuclear, cytoplasmic, or granule proteins) into the extracellular space. However, NETs have been recognized as key players in autoimmunity. SLE patients have higher numbers of a certain subset of neutrophils called low-density granulocytes (LDGs), which have increased ability to form NETs. These complexes are then taken up by plasmacytoid dendritic cells, inducing IFN-1 formation35 and enhancing IFN-1 production in human blood cells through a STING-dependent pathway.36 There is evidence that NETs can also target human memory B cells and activate them to create polyclonal IgG through TLR9. Indirectly, they can be internalized by B cells and presented on MHC-II to activate CD4+ T cells, further heightening adaptive immunity.37
The Importance of Immune Cells in the Pathogenesis Of NEC
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Andres Gonzalez Salazar, David J. Hackam
The relationship between neutrophils (PMNs) and NEC has been studied for the past 3 decades. Musemeche et al. initially concluded an important role for PMNs in NEC by depleting neutrophils with vinblastine in a platelet activator factor (PAF) and lipopolysaccharide (LPS) rat NEC model, which decreased the severity of intestinal injury (3). The role of PMNs in NEC received little attention, given the fact that histologic and flow cytometric evaluation of the human and mouse bowel with NEC is relatively PMN deficient (1). More recently, PMNs have been linked to the development of NEC through the formation of neutrophil extracellular traps (NETs). These are web-like structures made up of DNA that contain antimicrobial proteins and histones and are formed in the presence of virus, bacteria, and protozoa, where they bind to, immobilize, and eliminate microorganisms (4, 5). Studies have suggested that an excessive NET formation is crucial in the ischemic injury that ultimately leads to neutrophilic tissue damage (4). In both animal models and human neonates suffering from NEC, studies have demonstrated an increase in intestinal cell-free DNA (cfDNA) and neutrophilic proteins, markers of NET formation (5, 6). In further support of this association, more recent studies have hypothesized that impeding or dissolving NET formation may lead to reduced tissue injury and inflammation (7, 8). Treatment of mice NEC models with DNase1 and protein arginine deiminase (PAD), inhibitors of NETs, have been shown decreased NEC severity, further supporting these claims (9, 10).
Role of Vitamin C in Chronic Wound Healing
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Juliet M. Pullar, Margreet C.M. Vissers
Neutrophil extracellular traps (NETs) are web-like structures composed of granular proteins and nuclear material that are released from dying neutrophils via a process termed NETosis. They are postulated to immobilize bacteria and fungi and mediate the extracellular killing of pathogens [85,86]. A model of experimental sepsis in the Gulo−/− mouse found that vitamin C deficiency increased the generation of NETs in vivo, with vitamin C supplementation able to attenuate this response [70]. Experiments conducted with human neutrophils activated to release NETs also showed that preloading of cells with ascorbate reduced the formation of NETs [70]. Recent work in diabetic patients and animals models suggests NETs may have a role in delayed healing of wounds associated with diabetes [87,88]. Neutrophils from diabetics were primed to release NETs, overexpressing PAD4, an enzyme important in chromatin decondensation during NET release [87]. In mouse models of diabetes, pharmacologic inhibition or genetic knockout of NET formation accelerated wound healing. In humans, proteomic analysis showed NET proteins were elevated in the wounds of nonhealing diabetic foot ulcers compared to those that exhibited rapid healing, and biomarkers of NETs were elevated in the circulation of those with diabetic foot ulcers [88]. Interestingly, HIF-1α can regulate NET formation in response to lipopolysaccharide [89].
Neutrophil extracellular trap is an important connection between hemodialysis and acute myocardial infarction
Published in Renal Failure, 2023
Yue Yang, Yuan-yuan Jiao, Zheng Zhang, Li Zhuo, Wen-ge Li
Neutrophil extracellular traps (NETs) were first discovered as a novel immune defense mechanism of neutrophils [8], but they can also mediate tissue injury and sterile inflammation [9]. The process by which NETs are secreted by neutrophils is called NETosis, which is a form of inflammatory cell death of neutrophils that differs from common apoptosis and necrosis. When NETosis occurs, DNA strands extruded by activated or dead neutrophils are enhanced by various protein mediators to form a reticular structure with DNA as the main component [10]. Evidence accumulated in the past 20 years has shown that immune disorders played decisive roles in the initiation and development of the coronary artery disease (CAD) pathology process [11]. As one of the most important mechanisms, our view of thrombosis and atherosclerosis has changed significantly along with the emergence of NETs [9,12].
Anti-triple-negative breast cancer metastasis efficacy and molecular mechanism of the STING agonist for innate immune pathway
Published in Annals of Medicine, 2023
Xing Lu, Xiang Wang, Hao Cheng, Xiaoqing Wang, Chang Liu, Xiangshi Tan
In our current investigation, we tested the antitumour effect and toxicity of cGAMP by systematic administration in TNBC. The findings revealed that cGAMP activated innate and cross-primed adaptive immunity, increased and enhanced antigen-presenting activity of DCs, and activated CD8+T cells to effectively destroy tumours and reversed inhibitory immune microenvironment. It was worth noting that neutrophil and TAM, associated with metastasis, decreased in the treatment group. The bone marrow monocytes circulating in the blood differentiate into macrophages and become an important part of innate immunity. Monocytes enter tumour tissues and differentiate into tumour-associated macrophages (TAMs) under tumour microenvironment influence. The number of neutrophils and TAMs in patients is connected to tumour progression and patient survival, and cancer cells can hijack the host’s protective immune system, promoting further growth and metastasis [31]. Upon activation, neutrophils release a fibrous network-like structure named neutrophil extracellular traps (NETs), which are abundant in a variety of malignant tumours [70–72]. Currently, more pieces of evidence demonstrate that NETs can promote tumour progression and metastasis by destroying vascular integrity [73,74]. cGAMP-administration reduced the expression of neutrophils and TAM to protect the immune system, resulting in a significant reduction during lymph node and pulmonary metastasis.
Identification and Validation of Molecular Subtype and Prognostic Signature for Bladder Cancer Based on Neutrophil Extracellular Traps
Published in Cancer Investigation, 2023
Neutrophil extracellular traps (NETs) are filamentous structures composed of extracellular DNA, granular proteins, and histones [11]. As key players in innate immune response and pathological progress, NETs exert a vital role in many diseases, including myocardial infarction[12], periodontitis [13], atherosclerosis [14], rheumatoid arthritis [15]. Tumor cells could recruit neutrophils and release NETs to tumor microenvironment [16]. As far as we know, the role of NETs in cancer is complicated and far from elucidated. On the one hand, NETs could promote tumor relapse by awaking dormant cancer cells [17]. By secreting matrix metalloproteinases, NETs could facilitate tumor growth and distant metastases [18]. On the other hand, NET components, including myeloperoxidase and histones, could directly kill tumor cells [18,19]. Recent study revealed that NET-related signature could predict the clinical outcomes and immunotherapy response in certain type of cancer [20]. Jing et al identified a prognostic signature for ccRCC using NETs-related genes [21]. Another study constructed a NETs-associated lncRNA signature predicting the clinical outcomes in LUAD [22]. These evidences indicated that clarification of the crosstalk between BLCA and NETs may help to devise potential approaches for the prognosis and treatment of BLCA.