NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond - PMC - 0 views
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Pneumonia is a typical symptom of COVID-19 infection, while acute respiratory distress syndrome (ARDS) and multiple organ failure are common in severe COVID-19 patients
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NETs are important for preventing pathogen invasion, their excessive formation can result in a slew of negative consequences, such as autoimmune inflammation and tissue damage
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SARS-CoV-2 infection has also been linked to increased neutrophil-to-lymphocyte ratios, which is associated with disease severity and clinical prognosis
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NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)
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increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis
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Another indirect route of SARS-CoV-2-induced NET production is platelet activation
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When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis
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In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.
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SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors
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Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause
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NETosis and NETs are increasingly recognized as causes of vascular injury
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SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation
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NET formation may be caused by activated platelets rather than SARS-CoV-2 itself
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NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.
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early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses
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NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease
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NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation
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“cytokine storm”
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SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19
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NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response
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patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]
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COVID-19 NETs may act as potential inducers for autoimmune responses
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have weakened adaptive immunity as well as a high level of inflammation
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tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised
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NETs have also been shown to enhance macrophage pyroptosis in sepsis
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facilitating an immunosuppressive microenvironment
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persistent immunosuppression may result in bacterial co-infection or secondary infection
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can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes
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NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection
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Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness
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NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells
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decreased E-cadherin (an epithelial marker) expression
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COVID-19 also has a long-term influence on tumor progression
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Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19
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patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis
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awaken cancer cells
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NETs have been shown to change the tumor microenvironment
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enhance tumor progression and metastasis
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vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response
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vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS
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vitamin C may also inhibit NETosis and NET production in COVID-19
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Metformin
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Vitamin C
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NETosis intimately involved in progressive COVID, long COVID, autoimmunity, and cancer