Receptor-Mediated NETosis on Neutrophils

Chen, Tao; Li, Yanhong; Sun, Rui; Hu, Huifang; Liu, Yi; Herrmann, Martin; Zhao, Yi; Muñoz, Luis E.

doi:10.3389/fimmu.2021.775267

Cited by 65 publications

(37 citation statements)

References 89 publications

(106 reference statements)

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“…NETs are found to be presented only in incomplete atherosclerotic plaques, such as ruptures and erosions, including the adjacent tissues surrounding such plaques, but were not presented in intact plaques and their surrounding adjacent tissues [ 31 ]. TLR4 was significantly up-regulated in the NETs formation pathway, which is consistent with the findings of previous studies [ 32 ].…”

Section: Discussionsupporting

confidence: 92%

Transcriptomic Analysis Uncovers Immunogenic Characteristics of Ferroptosis for Myocardial Infarction and Potential Therapeutic Prediction of Chinese Herbs

Jiang

Zeng

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Inflammation and immune response play a key role in myocardial injury and repair after myocardial infarction (MI), while the relevant regulatory mechanisms of immune infiltration in MI have been fully explored. Ferroptosis is an iron-dependent form of regulated cell death characterized by an excessive accumulation of iron and lipid peroxides and involves in the pathogenesis of myocardial infarction. In the present study, by integrating intelligent data acquisition, data mining, network pharmacology, and computer-assisted target fishing, we developed a highly efficient system for screening immunity- and ferroptosis-related biomarkers and immunomodulatory ability of herbal ingredients. Results. Immune infiltration analysis of GSE97320 showed significant neutrophil infiltration in the myocardial infarction group compared to the healthy group, and 807 differentially expressed genes (DEGs) were obtained (526 up-regulated and 281 downregulated). Among these DEGs, 73 immune-related and 8 ferroptosis-related DEGs were obtained. Further protein-protein interaction network analysis revealed 30 hub genes. The DEGs were enriched in a total of 107 biological processes, of which neutrophil-related biological processes were the most significant, enriched in 31 cellular components such as bead-binding hemoglobin complex, hemoglobin complex, and enriched in 36 functions such as bead-binding hemoglobin complex and hemoglobin complex. The DEGs were also enriched in 21 KEGG pathways such as lipid-atherosclerosis and formation of neutrophil extracellular traps. Further analysis identified Toll-like receptor-4 (TLR4) as the key gene, and based on TLR4, 17 herbal ingredients and 6 herbal medicines were predicted by using HERB and Coremine databases. Further molecular docking analysis showed that TLR4 could bind to salvianolic acid b and stigmasterol. The molecular dynamics analysis revealed that TLR4 could bind to salvianolic acid b, stigmasterol, and resveratrol in the stable phase with the binding between TLR4 and salvianolic acid b being the most stable. Conclusions. TLR4 is a key gene that is related to ferroptosis and immune cell infiltration. Further analysis revealed that 17 herbal ingredients and 6 herbal medicines were predicted to have potential interactions with TLR4. These predicted herbal ingredients/medicines may act synergistically to protect against myocardial injury after MI through suppressing neutrophil extracellular traps. The protective effects may be associated with immune cell infiltration and ferroptosis.

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Section: Discussionsupporting

confidence: 92%

Transcriptomic Analysis Uncovers Immunogenic Characteristics of Ferroptosis for Myocardial Infarction and Potential Therapeutic Prediction of Chinese Herbs

Jiang

Zeng

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…NET-associated anti-myeloperoxidase antibodies, 3. anti-protein 3 antibodies in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) and ( 66 ) 4. NET-derived extracellular nucleic acids and dsDNA are the targets of systemic lupus erythematosus (SLE) autoantibodies ( 67 , 68 ). Interestingly, Hakkim and colleagues reported an impaired NET degradation in a subgroup of SLE patients based on either inhibition of DNase I or anti-NET antibodies, which prevent binding of DNase I to NETs.…”

Section: Discussionmentioning

confidence: 99%

Insights Into Immunothrombotic Mechanisms in Acute Stroke due to Vaccine-Induced Immune Thrombotic Thrombocytopenia

et al. 2022

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During the COVID-19 pandemic, vaccination is the most important countermeasure. Pharmacovigilance concerns however emerged with very rare, but potentially disastrous thrombotic complications following vaccination with ChAdOx1. Platelet factor-4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT) was described as an underlying mechanism of these thrombotic events. Recent work moreover suggests that mechanisms of immunothrombosis including neutrophil extracellular trap (NET) formation might be critical for thrombogenesis during VITT. In this study, we investigated blood and thrombus specimens of a female patient who suffered severe stroke due to VITT after vaccination with ChAdOx1 in comparison to 13 control stroke patients with similar clinical characteristics. We analyzed cerebral thrombi using histological examination, staining of complement factors, NET-markers, DNase and LL-37. In blood samples at the hyper-acute phase of stroke and 7 days later, we determined cell-free DNA, myeloperoxidase-histone complexes, DNase activity, myeloperoxidase activity, LL-37 and inflammatory cytokines. NET markers were identified in thrombi of all patients. Interestingly, the thrombus of the VITT-patient exclusively revealed complement factors and high amounts of DNase and LL-37. High DNase activity was also measured in blood, implying a disturbed NET-regulation. Furthermore, serum of the VITT-patient inhibited reactive oxygen species-dependent NET-release by phorbol-myristate-acetate to a lesser degree compared to controls, indicating either less efficient NET-inhibition or enhanced NET-induction in the blood of the VITT-patient. Additionally, the changes in specific cytokines over time were emphasized in the VITT-patient as well. In conclusion, insufficient resolution of NETs, e.g. by endogenous DNases or protection of NETs against degradation by embedded factors like the antimicrobial peptide LL-37 might thus be an important factor in the pathology of VITT besides increased NET-formation. On the basis of these findings, we discuss the potential implications of the mechanisms of disturbed NETs-degradation for diagnostic and therapeutic approaches in VITT-related thrombogenesis, other auto-immune disorders and beyond.

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“…PAD4 participates in NETs formation by altering the chromatin status through the cooperation with the neutrophil elastase (NE) and myeloperoxidase [ 35 ]. The resulting decondensed chromatin discharged into the extracellular space and leads to neutrophil death, in a process also called NOX-dependent NETosis [ 36 ].…”

Section: Sars-cov-2 Innate Immune System Responsementioning

confidence: 99%

Innate Immune Response in SARS-CoV-2 Infection

et al. 2022

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An efficient host immune response is crucial in controlling viral infections. Despite most studies focused on the implication of T and B cell response in COVID-19 (Corona Virus Disease-19) patients or in their activation after vaccination against SARS-CoV-2, host innate immune response has raised even more interest as well. In fact, innate immunity, including Natural Killer (NK) cells, monocytes/macrophages and neutrophils, represent the first line of defense against the virus and it is essential to determine the correct activation of an efficient and specific acquired immune response. In this perspective, we will report an overview on the main findings concerning SARS-CoV-2 interaction with innate host immune system, in correlation with pathogenesis and viral immune escape mechanisms.

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Receptor-Mediated NETosis on Neutrophils

Cited by 65 publications

References 89 publications

Transcriptomic Analysis Uncovers Immunogenic Characteristics of Ferroptosis for Myocardial Infarction and Potential Therapeutic Prediction of Chinese Herbs

Transcriptomic Analysis Uncovers Immunogenic Characteristics of Ferroptosis for Myocardial Infarction and Potential Therapeutic Prediction of Chinese Herbs

Insights Into Immunothrombotic Mechanisms in Acute Stroke due to Vaccine-Induced Immune Thrombotic Thrombocytopenia

Innate Immune Response in SARS-CoV-2 Infection

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