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Liao R, Wang L, Zeng J, Tang X, Huang M, Kantawong F, Huang Q, Mei Q, Huang F, Yang Y, Liao B, Wu A, Wu J. Reactive oxygen species: Orchestrating the delicate dance of platelet life and death. Redox Biol 2025; 80:103489. [PMID: 39764976 PMCID: PMC11759559 DOI: 10.1016/j.redox.2025.103489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 12/27/2024] [Accepted: 01/02/2025] [Indexed: 01/28/2025] Open
Abstract
Platelets, which are vital for blood clotting and immunity, need to maintain a delicately balanced relationship between generation and destruction. Recent studies have highlighted that reactive oxygen species (ROS), which act as second messengers in crucial signaling pathways, are crucial players in this dance. This review explores the intricate connection between ROS and platelets, highlighting their dual nature. Moderate ROS levels act as potent activators, promoting megakaryocyte (MK) differentiation, platelet production, and function. They enhance platelet binding to collagen, increase coagulation, and directly trigger cascades for thrombus formation. However, this intricate role harbors a double-edged sword. Excessive ROS unleash its destructive potential, triggering apoptosis and reducing the lifespan of platelets. High levels can damage stem cells and disrupt vital redox-dependent signaling, whereas uncontrolled activation promotes inappropriate clotting, leading to thrombosis. Maintaining a precise balance of ROS within the hematopoietic microenvironment is paramount for optimal platelet homeostasis. While significant progress has been made, unanswered questions remain concerning specific ROS signaling pathways and their impact on platelet disorders. Addressing these questions holds the key to unlocking the full potential of ROS-based therapies for treating platelet-related diseases such as thrombocytopenia and thrombosis. This review aims to contribute to this ongoing dialog and inspire further exploration of this exciting field, paving the way for novel therapeutic strategies that harness the benefits of ROS while mitigating their dangers.
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Affiliation(s)
- Rui Liao
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Long Wang
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Jing Zeng
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Xiaoqin Tang
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Miao Huang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Fahsai Kantawong
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Qianqian Huang
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Qibing Mei
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Feihong Huang
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Yan Yang
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
| | - Bin Liao
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
| | - Anguo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China.
| | - Jianming Wu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China.
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Zhou Q, Zhou X, Li J, Wang R, Xie F. Research progress on the relationship between neutrophil extra-cellular traps and autogenous arteriovenous fistula thrombosis. J Vasc Access 2025:11297298251317298. [PMID: 39935409 DOI: 10.1177/11297298251317298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Autogenous arteriovenous fistula (AVF) is the preferred vascular access for long-term hemodialysis, and thrombosis is one of the most common complications. In recent years, it has been found that neutrophil extra-cellular traps (NETs) play an important role in thrombosis. NETs are a kind of network structure with DNA as a skeleton and intercalated with a variety of granule proteins, proteolytic enzymes, antimicrobial peptides and histone proteins, which are released into the extracellular space by neutrophils after stimulation. In this paper, the NETs in the role of AVF thrombus formation and NETs in the value of prevention and cure of AVF thrombus complications were reviewed.
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Affiliation(s)
- Qi Zhou
- Department of Nephrology, The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xuhua Zhou
- Department of Nephrology, The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junlin Li
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Runxiu Wang
- Department of Nephrology, The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Fuhua Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
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3
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Wang Y, Mulder IA, Westendorp WF, Coutinho JM, van de Beek D. Immunothrombosis in Acute Ischemic Stroke. Stroke 2025; 56:553-563. [PMID: 39479751 DOI: 10.1161/strokeaha.124.048137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Ischemic stroke is one of the leading causes of disability and mortality worldwide. Thrombosis is the main pathological process of stroke and is therefore an important therapeutic target in stroke prevention. In recent years, with the development of endovascular treatment and therefore retrieving the thrombus for further investigation, evidence is accumulating that immune cells are inextricably linked to stroke pathogenesis. Circulating immune cells have been found to induce immunothrombosis, and they actively participate in the formation of the thrombus by promoting platelet recruitment and thrombin activation. Additionally, the formation of thromboinflammation leads to increased instability of atherosclerotic plaques. We review the concepts of stroke immunothrombosis and thromboinflammation and the effect of immune cells on vessel recanalization and patient outcome. In addition, we elaborate on the possible mechanism of immune cells being activated and participating in thrombosis in ischemic stroke.
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Affiliation(s)
- Yan Wang
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Inge A Mulder
- Department of Biomedical Engineering and Physics (I.A.M.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Microcirculation, the Netherlands (I.A.M.)
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Willeke F Westendorp
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Jonathan M Coutinho
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Diederik van de Beek
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
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4
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Yu F, Chen J, Zhang X, Ma Z, Wang J, Wu Q. Role of Neutrophil Extracellular Traps in Hypertension and Their Impact on Target Organs. J Clin Hypertens (Greenwich) 2025; 27:e14942. [PMID: 39686847 PMCID: PMC11771816 DOI: 10.1111/jch.14942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 10/27/2024] [Accepted: 10/29/2024] [Indexed: 12/18/2024]
Abstract
Hypertension is the predominant cause of cardiovascular diseases (CVDs) globally, and essential hypertension (EH) represents a significant public health challenge due to its multifactorial etiology involving complex interactions between genetic and environmental factors. However, the pathogenesis of EH is still unclear. Hypertension is a dysregulation in the renin-angiotensin-aldosterone system and sympathetic nervous system, both regulating saline homeostasis and cardiovascular function. However, current therapeutic interventions targeting these systems have limited efficacy in approximately 40% of cases, suggesting the involvement of alternative mechanisms. Inflammation is associated with the occurrence and progression of hypertension, but the underlying mechanism remains elusive, while chronic inflammation leads to tissue damage, fibrosis, and irreversible organ dysfunction. The development and maintenance of EH are caused by endothelial dysfunction, oxidative stress, and chronic inflammation. Neutrophils are involved in both acute and chronic inflammation since they represent the primary line of defense against inflammatory insults once recruited to the inflamed site where they remove harmful impurities. The process involving the formation of neutrophil extracellular traps (NETs) is called NETosis are involved in the pathogenesis and progression of CVDs, including coronary artery disease, acute myocardial infarction, peripheral arterial disease, heart failure, and atrial fibrillation. Recent investigations demonstrated that NETs facilitate the development of hypertension; however, the precise role of NETs in hypertension remains largely elusive. Therefore, this review aims to provide an overview of the current understanding regarding the involvement of NETosis in hypertension and explore the potential therapies targeting NETs for future interventions.
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Affiliation(s)
- Fei Yu
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Jianshu Chen
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Xiaowei Zhang
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Zhengke Ma
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Jingtao Wang
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Qiang Wu
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
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Marta-Enguita J, Machado FJD, Orbe J, Muñoz R. Thrombus composition and its implication in ischemic stroke assessment and revascularization treatments. Neurologia 2025; 40:77-88. [PMID: 39716574 DOI: 10.1016/j.nrleng.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/01/2022] [Indexed: 12/25/2024] Open
Abstract
INTRODUCTION Since mechanical thrombectomy has allowed ischaemic stroke thrombus retrieval, the exhaustive study of this material has enabled better understanding of the potential physiopathological processes involved in thrombus formation. DEVELOPMENT Thrombotic pathways involved in the different vascular beds share common mechanisms, causing difficulties in the identification of specific patterns associated with stroke aetiology. However, other factors such as clot formation time, associated inflammatory status, or activation of additional immune and coagulation pathways (neutrophil extracellular trap [NET] delivery, platelet aggregation, endothelial activation, and von Willebrand Factor release) have been described as determinants in thrombus characteristics. Thus, variable proportions of fibrin-/platelet-rich and erythrocyte-rich areas are closely interrelated within the thrombus, frequently associated with a protective outer shell with high concentrations of fibrin, NETs, and von Willebrand Factor. The presence of these components, as well as their distribution and interrelationships, have been shown to have effects on the thrombus' resistance to revascularisation treatments. Understanding of these pathways has enabled the development of adjuvant therapies capable of enhancing current fibrinolytic drugs and/or increasing the efficacy of endovascular treatments. CONCLUSION Understanding of thrombus components and mechanisms involved in thrombus formation represent a potential pathway for the development of ischaemic stroke therapeutics with promising perspectives.
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Affiliation(s)
- Juan Marta-Enguita
- Servicio de Neurología, Hospital Universitario Navarra, Pamplona, Navarra, Spain; Servicio de Neurología, Hospital Universitario Donostia, San Sebastián, Guipúzcoa, Spain; Laboratorio Aterotrombosis, CIMA-Universidad de Navarra, IdiSNA, Pamplona, Navarra, Spain; RICORS-ICTUS, ISCIII, Madrid, Spain.
| | - Florencio J D Machado
- Laboratorio Aterotrombosis, CIMA-Universidad de Navarra, IdiSNA, Pamplona, Navarra, Spain
| | - Josune Orbe
- Laboratorio Aterotrombosis, CIMA-Universidad de Navarra, IdiSNA, Pamplona, Navarra, Spain; RICORS-ICTUS, ISCIII, Madrid, Spain
| | - Roberto Muñoz
- Servicio de Neurología, Hospital Universitario Navarra, Pamplona, Navarra, Spain; RICORS-ICTUS, ISCIII, Madrid, Spain
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Wang N, Shi XL, Li D, Li BB, Liu P, Luo H. Neutrophil extracellular traps - an a-list-actor in a variety of diseases. Ann Hematol 2024; 103:5059-5069. [PMID: 39078437 DOI: 10.1007/s00277-024-05915-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/25/2024] [Indexed: 07/31/2024]
Abstract
Neutrophil extracellular traps (NETs) represent a response mechanism in which activated neutrophils release DNA-based webs, adorned with histones and neutrophil proteases, to capture and eliminate invasive microorganisms. However, when these neutrophils become excessively activated, much more proteases associated with NETs are liberated into surrounding tissues or bloodstreams, thereby altering the cellular milieu and causing tissue damage. Recent research has revealed that NETs may play significant roles in the emergence and progression of various diseases, spanning from infections, inflammation to autoimmune disorders and cancers. In this review, we delve deeply into the intricate and complex mechanisms that underlie the formation of NETs and their profound interplay with various clinical pathologies. We aim to describe the application perspectives of NETs related proteins in specific disease diagnosis and treatment.
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Affiliation(s)
- Na Wang
- College of Medical Laboratory, Dalian Medical University, Dalian, Liaoning, 116044, PR China
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
| | - Xiao-Lin Shi
- Department of Clinical Laboratory, Weihai Maternal and Child Health Hospital, Weihai, Shandong, 264200, PR China
| | - Dan Li
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
| | - Bin-Bin Li
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
| | - Peng Liu
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China.
| | - Hong Luo
- College of Medical Laboratory, Dalian Medical University, Dalian, Liaoning, 116044, PR China.
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Madison MC, Finley DC, Genschmer KR. In a sticky situation: pro-coagulant properties expand the importance of neutrophil EVs in driving tissue injury. J Leukoc Biol 2024; 116:1220-1222. [PMID: 39171927 DOI: 10.1093/jleuko/qiae185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 08/20/2024] [Indexed: 08/23/2024] Open
Abstract
Inflammatory and microbial stimuli prompt a neutrophil extracellular vesicle signature capable of driving disease processes.
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Affiliation(s)
- Matthew C Madison
- Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, 1720 2nd Ave. South, Birmingham, AL 35294, United States
- Program in Lung Biology Lung Health Center, University of Alabama at Birmingham, 1720 2nd Ave. South, Birmingham, AL 35294, United States
| | - Dakota C Finley
- Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, 1720 2nd Ave. South, Birmingham, AL 35294, United States
| | - Kristopher R Genschmer
- Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, 1720 2nd Ave. South, Birmingham, AL 35294, United States
- Program in Lung Biology Lung Health Center, University of Alabama at Birmingham, 1720 2nd Ave. South, Birmingham, AL 35294, United States
- Program in Protease and Matrix Biology, University of Alabama at Birmingham, 1720 2nd Ave. South, Birmingham, AL 35294, United States
- Gregory Fleming James Cystic Fibrosis Center, University of Alabama at Birmingham, 1720 2nd Ave. South, Birmingham, AL 35294, United States
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Baumann T, de Buhr N, Blume N, Gabriel MM, Ernst J, Fingerhut L, Imker R, Abu-Fares O, Kühnel M, Jonigk DD, Götz F, Falk C, Weissenborn K, Grosse GM, Schuppner R. Assessment of associations between neutrophil extracellular trap biomarkers in blood and thrombi in acute ischemic stroke patients. J Thromb Thrombolysis 2024; 57:936-946. [PMID: 38853210 PMCID: PMC11315804 DOI: 10.1007/s11239-024-03004-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2024] [Indexed: 06/11/2024]
Abstract
Inflammation including immunothrombosis by neutrophil extracellular traps (NETs) has important implications in acute ischemic stroke and can affect reperfusion status, susceptibility to stroke associated infections (SAI) as well as functional clinical outcome. NETs were shown to be prevalent in stroke thrombi and NET associated markers were found in stroke patients' blood. However, little is known whether blood derived NET markers reflect the amount of NETs in thrombi. Conclusions from blood derived markers to thrombus composition might open avenues for novel strategies in diagnostic and therapeutic approaches. We prospectively recruited 166 patients with acute ischemic stroke undergoing mechanical thrombectomy between March 2018 and May 2021. Available thrombi (n = 106) were stained for NET markers DNA-histone-1 complexes and myeloperoxidase (MPO). Cell free DNA (cfDNA), deoxyribonuclease (DNase) activity, MPO-histone complexes and a cytokine-panel were measured before thrombectomy and after seven days. Clinical data, including stroke etiology, reperfusion status, SAI and functional outcome after rehabilitation, were collected of all patients. NET markers were present in all thrombi. At onset the median concentration of cfDNA in blood was 0.19 µg/ml increasing to 0.30 µg/ml at 7 days. Median DNase activity at onset was 4.33 pmol/min/ml increasing to 4.96 pmol/min/ml at 7 days. Within thrombi DNA-histone-1 complexes and MPO correlated with each other (ρ = 0.792; p < 0.001). Moreover, our study provides evidence for an association between the amount of NETs and endogenous DNase activity in blood with amounts of NETs in cerebral thrombi. However, these associations need to be confirmed in larger cohorts, to investigate the potential clinical implications for individualized therapeutic and diagnostic approaches in acute ischemic stroke.
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Affiliation(s)
- Tristan Baumann
- Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Nicole de Buhr
- Institute of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
| | - Nicole Blume
- Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Maria M Gabriel
- Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Johanna Ernst
- Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Leonie Fingerhut
- Institute of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
| | - Rabea Imker
- Institute of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
| | - Omar Abu-Fares
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Mark Kühnel
- Institute of Pathology, Hannover Medical School, Hannover, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
| | - Danny D Jonigk
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
- Institute of Pathology, RWTH Aachen Medical University, Aachen, Germany
| | - Friedrich Götz
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Christine Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Karin Weissenborn
- Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Gerrit M Grosse
- Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
- Department of Neurology and Stroke Center, University Hospital Basel, Basel, Switzerland
| | - Ramona Schuppner
- Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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Li W, Chi D, Ju S, Zhao X, Li X, Zhao J, Xie H, Li Y, Jin J, Mang G, Dong Z. Platelet factor 4 promotes deep venous thrombosis by regulating the formation of neutrophil extracellular traps. Thromb Res 2024; 237:52-63. [PMID: 38547695 DOI: 10.1016/j.thromres.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 02/14/2024] [Accepted: 03/04/2024] [Indexed: 04/29/2024]
Abstract
The presence of neutrophil extracellular traps (NETs) in thrombotic diseases has been extensively studied. The exact mechanism of NET formation in deep venous thrombosis (DVT) has not been largely studied. This study is aimed to explore the role of NETs and their interaction with platelet factor 4 (PF4) in DVT. In plasma samples from 51 healthy volunteers and 52 DVT patients, NET markers and PF4 were measured using enzyme-linked immunosorbent assays (ELISA). NET generation in blood samples from healthy subjects and DVT patients was analyzed by confocal microscopy and flow cytometry. The plasma levels of NETs were significantly elevated in DVT patients, and neutrophils from patients showed a stronger ability to generate NETs after treatment. PF4 was upregulated in plasma samples from DVT patients and mediated NET formation. NETs enhanced procoagulant (PCA) via tissue factor and activating platelets to induce procoagulant activity. In addition, we established an inferior vena cava ligation (IVC) model to examine the role of NETs in thrombogenicity in DVT. In conclusion, NET formation was mediated by PF4 and enhance the procoagulant activity in DVT.
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Affiliation(s)
- Wenqiang Li
- Department of Vascular and Wound Center, Jinshan Hospital of Fudan University, Shanghai, China.
| | - Decai Chi
- Department of Vascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuai Ju
- Department of Vascular and Wound Center, Jinshan Hospital of Fudan University, Shanghai, China
| | - Xinyi Zhao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoyan Li
- Department of Vascular and Wound Center, Jinshan Hospital of Fudan University, Shanghai, China
| | - Junjie Zhao
- Department of General Surgery, The Fourth Hospital of Changsha City, Changsha, China
| | - Huiqi Xie
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yao Li
- Department of Vascular and Wound Center, Jinshan Hospital of Fudan University, Shanghai, China
| | - Jiaqi Jin
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Ge Mang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Zhihui Dong
- Department of Vascular and Wound Center, Jinshan Hospital of Fudan University, Shanghai, China; Department of Vascular Surgery, Zhongshan hospital of Fudan University, Shanghai, China.
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10
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Nowaczewska-Kuchta A, Ksiazek-Winiarek D, Szpakowski P, Glabinski A. The Role of Neutrophils in Multiple Sclerosis and Ischemic Stroke. Brain Sci 2024; 14:423. [PMID: 38790402 PMCID: PMC11118671 DOI: 10.3390/brainsci14050423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Inflammation plays an important role in numerous central nervous system (CNS) disorders. Its role is ambiguous-it can induce detrimental effects, as well as repair and recovery. In response to injury or infection, resident CNS cells secrete numerous factors that alter blood-brain barrier (BBB) function and recruit immune cells into the brain, like neutrophils. Their role in the pathophysiology of CNS diseases, like multiple sclerosis (MS) and stroke, is highly recognized. Neutrophils alter BBB permeability and attract other immune cells into the CNS. Previously, neutrophils were considered a homogenous population. Nowadays, it is known that various subtypes of these cells exist, which reveal proinflammatory or immunosuppressive functions. The primary goal of this review was to discuss the current knowledge regarding the important role of neutrophils in MS and stroke development and progression. As the pathogenesis of these two disorders is completely different, it gives the opportunity to get insight into diverse mechanisms of neutrophil involvement in brain pathology. Our understanding of the role of neutrophils in CNS diseases is still evolving as new aspects of their activity are being unraveled. Neutrophil plasticity adds another level to their functional complexity and their importance for CNS pathophysiology.
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Affiliation(s)
| | | | | | - Andrzej Glabinski
- Department of Neurology and Stroke, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland; (A.N.-K.); (D.K.-W.); (P.S.)
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11
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Fang H, Bo Y, Hao Z, Mang G, Jin J, Wang H. A promising frontier: targeting NETs for stroke treatment breakthroughs. Cell Commun Signal 2024; 22:238. [PMID: 38654328 PMCID: PMC11036592 DOI: 10.1186/s12964-024-01563-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 03/07/2024] [Indexed: 04/25/2024] Open
Abstract
Stroke is a prevalent global acute cerebrovascular condition, with ischaemic stroke being the most frequently occurring type. After a stroke, neutrophils accumulate in the brain and subsequently generate and release neutrophil extracellular traps (NETs). The accumulation of NETs exacerbates the impairment of the blood‒brain barrier (BBB), hampers neovascularization, induces notable neurological deficits, worsens the prognosis of stroke patients, and can facilitate the occurrence of t-PA-induced cerebral haemorrhage subsequent to ischaemic stroke. Alternative approaches to pharmacological thrombolysis or endovascular thrombectomy are being explored, and targeting NETs is a promising treatment that warrants further investigation.
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Affiliation(s)
- Huijie Fang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yunfei Bo
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Zhongfei Hao
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Ge Mang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiaqi Jin
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Hongjun Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
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12
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Wu ZR, Zhou TQ, Ai SC. Neutrophil extracellular traps correlate with severity and prognosis in patients with ischemic stroke: a systematic review and meta-analysis. Acta Neurol Belg 2024; 124:513-522. [PMID: 37950825 DOI: 10.1007/s13760-023-02409-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 10/12/2023] [Indexed: 11/13/2023]
Abstract
BACKGROUND AND OBJECTIVE A correlation between neutrophil extracellular traps (NETs) and ischemic stroke (IS) has been hypothesized, but the results of relevant studies remain controversial. The purpose was to determine whether NETs have an impact on ischemic stroke. METHODS The studies on the correlation between NETs and IS were retrieved from CNKI, Wanfang Data, VIP, CBM, PubMed, Web of Science, Embase, and Cochrane databases by computer from the start of the database to December 2022. The study adhered to PRISMA guidelines. The PICOS model was used to create inclusion criteria. Two researchers screened the literature and extracted the relevant data. The quality of the included studies was evaluated using the NOS and the 11 items recommended by the AHRQ, and meta-analysis was completed using Stata 15.1 software. RESULTS The researchers included 752 patients in 7 studies (4 case-control studies and 3 cross-sectional studies). The meta-analysis found NETs are positively associated with the severity of IS at the time of onset [r(95% CI) = 0.31(0.24, 0.38), P < 0.001]. NETs are positively associated with a worse prognosis of IS [r(95% CI) = 0.34(0.13, 0.53), P = 0.003]. CONCLUSION The presence of NETs is positively related to the severity and prognosis of IS. Higher levels of NETs indicate a more severe disease and a poorer prognosis. Because the number and quality of included studies are limited, the above results must be supported by further high-quality studies. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/ , identifier: CRD42022356619.
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Affiliation(s)
- Zhuo-Rao Wu
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Tian-Qi Zhou
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Shuang-Chun Ai
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
- Department of Rehabilitation, Mianyang Hospital, Chengdu University of Traditional Chinese Medicine, Mianyang, 621053, China.
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13
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Deng G, Zou X, Liu Z, Ren H, Li Y, Chen B, Zhang J. The protective effect of DNase I in retinal vein occlusion. BIOMOLECULES & BIOMEDICINE 2024; 24:387-394. [PMID: 37838927 PMCID: PMC10950336 DOI: 10.17305/bb.2023.9780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/05/2023] [Accepted: 10/12/2023] [Indexed: 10/16/2023]
Abstract
Retinal vein occlusion (RVO) ranks as the second most prevalent retinal vascular disease, following diabetic retinopathy. Neutrophil extracellular traps (NETs) play an important role in vascular diseases. This study aimed to elucidate the relationship between NETs and RVO, and to discern the potential role of deoxyribonuclease I (DNase I) in the prevention and treatment of RVO through the modulation of NETs. We analyzed circulating NETs biomarkers, namely cell-free DNA (cf-DNA), myeloperoxidase (MPO)-DNA, and neutrophil elastase (NE), in 30 RVO patients and 30 healthy individuals. We established an RVO mouse model using a retinal laser, and the mice were categorized into two groups: the DNase I group and the control group. Retinal images were taken at predetermined time points, and the state of the retinal vessels was assessed. Both tissue and blood samples were harvested for analysis of NETs expression through methods such as western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Our finding indicate an increase in circulating NETs biomarkers in human and mouse RVO cases, while also verifying the presence of NETs in the retinal thrombus of the RVO model. Both in vitro and in vivo tests revealed that DNase I attenuated NETs formation. Moreover, DNase I injections led to diminished NETs biomarker levels and a reduced duration of the thrombus after the RVO model establishment. Consequently, DNase I, a well-established modulator of NETs formation, might exhibit protective properties in the prevention and treatment of RVO.
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Affiliation(s)
- Guohua Deng
- Department of Ophthalmology, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
| | - Xi Zou
- Department of Ophthalmology, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
| | - Zhinan Liu
- Department of Ophthalmology, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
| | - Hang Ren
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanting Li
- Department of Ophthalmology, Suzhou Eye and ENT Hospital, Suzhou, China
| | - Bin Chen
- Department of Ophthalmology, Suzhou Eye and ENT Hospital, Suzhou, China
| | - Jun Zhang
- Department of Ophthalmology, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
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Sacchetti S, Puricelli C, Mennuni M, Zanotti V, Giacomini L, Giordano M, Dianzani U, Patti G, Rolla R. Research into New Molecular Mechanisms in Thrombotic Diseases Paves the Way for Innovative Therapeutic Approaches. Int J Mol Sci 2024; 25:2523. [PMID: 38473772 DOI: 10.3390/ijms25052523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/12/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Thrombosis is a multifaceted process involving various molecular components, including the coagulation cascade, platelet activation, platelet-endothelial interaction, anticoagulant signaling pathways, inflammatory mediators, genetic factors and the involvement of various cells such as endothelial cells, platelets and leukocytes. A comprehensive understanding of the molecular signaling pathways and cell interactions that play a role in thrombosis is essential for the development of precise therapeutic strategies for the treatment and prevention of thrombotic diseases. Ongoing research in this field is constantly uncovering new molecular players and pathways that offer opportunities for more precise interventions in the clinical setting. These molecular insights into thrombosis form the basis for the development of targeted therapeutic approaches for the treatment and prevention of thrombotic disease. The aim of this review is to provide an overview of the pathogenesis of thrombosis and to explore new therapeutic options.
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Affiliation(s)
- Sara Sacchetti
- Clinical Chemistry Laboratory, "Maggiore della Carità" University Hospital, Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy
| | - Chiara Puricelli
- Clinical Chemistry Laboratory, "Maggiore della Carità" University Hospital, Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy
| | - Marco Mennuni
- Division of Cardiology, "Maggiore della Carità" University Hospital, Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy
| | - Valentina Zanotti
- Clinical Chemistry Laboratory, "Maggiore della Carità" University Hospital, Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy
| | - Luca Giacomini
- Clinical Chemistry Laboratory, "Maggiore della Carità" University Hospital, Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy
| | - Mara Giordano
- Clinical Chemistry Laboratory, "Maggiore della Carità" University Hospital, Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy
| | - Umberto Dianzani
- Clinical Chemistry Laboratory, "Maggiore della Carità" University Hospital, Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy
| | - Giuseppe Patti
- Division of Cardiology, "Maggiore della Carità" University Hospital, Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy
| | - Roberta Rolla
- Clinical Chemistry Laboratory, "Maggiore della Carità" University Hospital, Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy
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15
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Zhu S, Yu Y, Hong Q, Li C, Zhang H, Guo K. Neutrophil Extracellular Traps Upregulate p21 and Suppress Cell Cycle Progression to Impair Endothelial Regeneration after Inflammatory Lung Injury. J Clin Med 2024; 13:1204. [PMID: 38592032 PMCID: PMC10931969 DOI: 10.3390/jcm13051204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/23/2024] [Accepted: 02/10/2024] [Indexed: 04/10/2024] Open
Abstract
Background: Sepsis is a major cause of ICU admissions, with high mortality and morbidity. The lungs are particularly vulnerable to infection and injury, and restoration of vascular endothelial homeostasis after injury is a crucial determinant of outcome. Neutrophil extracellular trap (NET) release strongly correlates with the severity of lung tissue damage. However, little is known about whether NETs affect endothelial cell (EC) regeneration and repair. Methods: Eight- to ten-week-old male C57BL/6 mice were injected intraperitoneally with a sublethal dose of LPS to induce acute lung inflammatory injury or with PBS as a control. Blood samples and lung tissues were collected to detect NET formation and lung endothelial cell proliferation. Human umbilical vein endothelial cells (HUVECs) were used to determine the role of NETs in cell cycle progression in vitro. Results: Increased NET formation and impaired endothelial cell proliferation were observed in mice with inflammatory lung injury following septic endotoxemia. Degradation of NETs with DNase I attenuated lung inflammation and facilitated endothelial regeneration. Mechanistically, NETs induced p21 upregulation and cell cycle stasis to impair endothelial repair. Conclusions: Our findings suggest that NET formation impairs endothelial regeneration and vascular repair through the induction of p21 and cell cycle arrest during inflammatory lung injury.
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Affiliation(s)
- Shuainan Zhu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (S.Z.); (Y.Y.); (Q.H.); (C.L.)
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai 210000, China
| | - Ying Yu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (S.Z.); (Y.Y.); (Q.H.); (C.L.)
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai 210000, China
| | - Qianya Hong
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (S.Z.); (Y.Y.); (Q.H.); (C.L.)
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai 210000, China
| | - Chenning Li
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (S.Z.); (Y.Y.); (Q.H.); (C.L.)
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai 210000, China
| | - Hao Zhang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (S.Z.); (Y.Y.); (Q.H.); (C.L.)
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai 210000, China
| | - Kefang Guo
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (S.Z.); (Y.Y.); (Q.H.); (C.L.)
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai 210000, China
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16
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Liu X, Hu Y, Yu X, Tan Y, Yu F, Chen M, Zhao M. Differential contributions of the C5b-9 and C5a/C5aR pathways to microvascular and macrovascular thrombosis in complement-mediated thrombotic microangiopathy patients. Clin Immunol 2024; 259:109871. [PMID: 38101498 DOI: 10.1016/j.clim.2023.109871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 10/18/2023] [Accepted: 10/31/2023] [Indexed: 12/17/2023]
Abstract
To clarify the role of the C5a/C5aR (C5a receptor) and C5b-9 pathways in macrovascular thrombosis (MAT) and renal microthrombosis (MIT), 73 renal biopsy-proven complement-mediated thrombotic microangiopathy (C-TMA) patients were enrolled; 9 patients with pure MAT and 13 patients with pure MIT were selected for further study. Twenty-five external C-TMA patients were selected as the validation cohort. Plasma C5a and sC5b-9 (soluble C5b-9) levels were significantly higher in patients with MAT than in those with MIT (P = 0.008, P = 0.041, respectively). The mean optical density of C5aR1 in the kidney was significantly higher in MAT patients than in those with MIT (P < 0.001). Both urinary sC5b-9 levels (MIT: P < 0.001, MAT: P = 0.004) and renal deposition of C5b-9 (MIT: P < 0.001, MAT: P = 0.001) were significantly higher in C-TMA patients compared to normal control, but were similar between MAT and MIT groups. In the correlation analysis within 22C-TMA patients, urinary sC5b-9 levels and renal deposition of C5b-9 were positively correlated to renal MIT formation (P = 0.009 and P = 0.031, respectively). Furthermore, the renal citrullinated histone H3 (CitH3)- and neutrophil elastase (NE)-positive area ratios were both significantly higher in the MAT group than in the MIT group (P = 0.006 and P = 0.020, respectively). Therefore, the local C5b-9 and C5a/C5aR1 pathways might have differential contributions to MIT and MAT formation in the disease.
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Affiliation(s)
- Xiaotian Liu
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology; Key laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing 100034, PR China
| | - Yifang Hu
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology; Key laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing 100034, PR China
| | - Xiaojuan Yu
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology; Key laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing 100034, PR China
| | - Ying Tan
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology; Key laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing 100034, PR China
| | - Feng Yu
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology; Key laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing 100034, PR China; Department of Nephrology, Peking University International Hospital, Beijing 102206, PR China.
| | - Min Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology; Key laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing 100034, PR China
| | - Minghui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology; Key laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing 100034, PR China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100034, PR China
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17
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Gao X, Zhao X, Li J, Liu C, Li W, Zhao J, Li Z, Wang N, Wang F, Dong J, Yan X, Zhang J, Hu X, Jin J, Mang G, Ma R, Hu S. Neutrophil extracellular traps mediated by platelet microvesicles promote thrombosis and brain injury in acute ischemic stroke. Cell Commun Signal 2024; 22:50. [PMID: 38233928 PMCID: PMC10795390 DOI: 10.1186/s12964-023-01379-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 11/01/2023] [Indexed: 01/19/2024] Open
Abstract
AIMS Neutrophil extracellular traps (NETs) have been implicated in thrombotic diseases. There is no definitive explanation for how NETs form during acute ischemic strokes (AIS). The purpose of our study was to investigate the potential mechanism and role of NETs formation in the AIS process. METHODS As well as 45 healthy subjects, 45 patients with AIS had ELISA tests performed to detect NET markers. Expression of high-mobility group box 1 (HMGB1) on platelet microvesicles (PMVs) was analyzed by flow cytometry in healthy subjects and AIS patients' blood samples. We established middle cerebral artery occlusion (MCAO) mice model to elucidate the interaction between PMPs and NETs. RESULTS A significant elevation in NET markers was found in patient plasma in AIS patients, and neutrophils generated more NETs from patients' neutrophils. HMGB1 expression was upregulated on PMVs from AIS patients and induced NET formation. NETs enhanced Procoagulant activity (PCA) through tissue factor and via platelet activation. Targeting lactadherin in genetical and in pharmacology could regulate the formation of NETs in MCAO model. CONCLUSIONS NETs mediated by PMVs derived HMGB1 exacerbate thrombosis and brain injury in AIS. Video Abstract.
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Affiliation(s)
- Xin Gao
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinyi Zhao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Jiacheng Li
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Chang Liu
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Wenqiang Li
- Department of Vascular Surgery, Jinshan Hospital of Fudan University, Shanghai, China
| | - Junjie Zhao
- Department of General Surgery, Changsha Fourth Hospital, Changsha, China
| | - Zhixi Li
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Nan Wang
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fang Wang
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiawei Dong
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiuwei Yan
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiheng Zhang
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xueyan Hu
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiaqi Jin
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
| | - Ge Mang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, Heilongjiang Province, China.
| | - Ruishuang Ma
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Ningbo University, Ningbo, China.
- Department of Radiotherapy and Chemotherapy, Ningbo First Hospital of Ningbo, Ningbo, 315000, China.
| | - Shaoshan Hu
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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18
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Denorme F, Ajanel A, Campbell RA. Immunothrombosis in neurovascular disease. Res Pract Thromb Haemost 2024; 8:102298. [PMID: 38292352 PMCID: PMC10825058 DOI: 10.1016/j.rpth.2023.102298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 02/01/2024] Open
Abstract
A State of the Art lecture titled "Immunothrombosis in Neurovascular Diseases" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Despite significant clinical advancements in stroke therapy, stroke remains a prominent contributor to both mortality and disability worldwide. Brain injury resulting from an ischemic stroke is a dynamic process that unfolds over time. Initially, an infarct core forms due to the abrupt and substantial blockage of blood flow. In the subsequent hours to days, the surrounding tissue undergoes gradual deterioration, primarily driven by sustained hypoperfusion, programmed cell death, and inflammation. While anti-inflammatory strategies have proven highly effective in experimental models of stroke, their successful translation to clinical use has proven challenging. To overcome this translational hurdle, a better understanding of the distinct immune response driving ischemic stroke brain injury is needed. In this review article, we give an overview of current knowledge regarding the immune response in ischemic stroke and the contribution of immunothrombosis to this process. We discuss therapeutic approaches to overcome detrimental immunothrombosis in ischemic stroke and how these can be extrapolated to other neurovascular diseases, such as Alzheimer's disease and multiple sclerosis. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.
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Affiliation(s)
- Frederik Denorme
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Division of Vascular Neurology, Department of Neurology, University of Utah, Salt Lake City, Utah, USA
| | - Abigail Ajanel
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Division of Microbiology and Pathology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Robert A. Campbell
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Division of Microbiology and Pathology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
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Wang Z, Yang F, He Z, Liang C. Light-induced circadian rhythm disorder leads to microvascular dysfunction via up-regulating NETs. Microvasc Res 2023; 150:104592. [PMID: 37567437 DOI: 10.1016/j.mvr.2023.104592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/31/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023]
Abstract
Circadian rhythm is a physical, mental, and behavioral pattern over the course of 24-hour cycle, and its disturbance is associated with increased risk of cardiovascular diseases. Microvascular dysfunction serves as an important cause of cardiovascular disease, but the relationship between rhythm disturbances and microcirculation remains elusive. Herein, we constructed the mice model of circadian rhythm disturbance and investigated the alterations of microvascular conditions. It was revealed that coronary microcirculatory function and cardiac diastolic function were significantly reduced, along with endothelium-dependent diastolic function of microvessels remarkably impaired in the rhythm-disordered group of mice compared to the control group. Notably, rhythm disturbance led to a significant upregulation of neutrophil extracellular traps (NETs) levels in mice, which cause endothelial dysfunction by inhibiting microvascular endothelial cell activity and migration capacity as well as inducing apoptosis. Additionally, intraperitoneal injection of Cl-amidine suppressed the production of NETs, which further improved coronary microcirculatory function and endothelium-dependent diastolic function. In conclusion, this study demonstrated that circadian rhythm disorders could induce the development of coronary microvascular dysfunction (CMD) through the up-regulation of NETs, providing a potential therapeutic direction for the treatment of CMD.
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Affiliation(s)
- Zhanhui Wang
- Department of Cardiology, Second Affiliated Hospital of Naval Medical University, Shanghai, China; Department of Health Care Section, 971th Hospital of PLA, Qingdao, China
| | - Fupeng Yang
- Department of Cardiology, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Zhiqing He
- Department of Cardiology, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
| | - Chun Liang
- Department of Cardiology, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
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20
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Kmeťová K, Lonina E, Yalavarthi S, Levine JS, Hoy CK, Sarosh C, Gockman K, Morris AE, Tambralli A, Madison JA, Zuo Y, Subang R, Rauch J, Knight JS. Interaction of the antiphospholipid syndrome autoantigen beta-2 glycoprotein I with DNA and neutrophil extracellular traps. Clin Immunol 2023; 255:109714. [PMID: 37527733 PMCID: PMC11200149 DOI: 10.1016/j.clim.2023.109714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/03/2023]
Abstract
Beta-2 glycoprotein I (β2GPI) is a phospholipid-binding plasma protein and prominent autoantigen in antiphospholipid syndrome (APS). Here, we tested the hypothesis that β2GPI might bind to not only phospholipids, but also cell-free DNA and neutrophil extracellular traps (NETs). We report that β2GPI interacts with cell-free DNA from different species, as well as NETs, in a dose-dependent manner, retarding their migration in an agarose-gel electrophoretic mobility shift assay. We confirm the direct binding interaction of β2GPI with DNA and NETs by ELISA. We also demonstrate that β2GPI colocalizes with NET strands by immunofluorescence microscopy. Finally, we provide evidence that β2GPI-DNA complexes can be detected in the plasma of APS patients, where they positively correlate with an established biomarker of NET remnants. Taken together, our findings indicate that β2GPI interacts with DNA and NETs, and suggest that this interaction may play a role as a perpetuator and/or instigator of autoimmunity in APS.
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Affiliation(s)
- Katarína Kmeťová
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Elena Lonina
- Division of Rheumatology, Department of Medicine, McGill University, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Srilakshmi Yalavarthi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jerrold S Levine
- Section of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA
| | - Claire K Hoy
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Cyrus Sarosh
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Kelsey Gockman
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Alexandra E Morris
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Ajay Tambralli
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jacqueline A Madison
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Yu Zuo
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Rebecca Subang
- Division of Rheumatology, Department of Medicine, McGill University, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Joyce Rauch
- Division of Rheumatology, Department of Medicine, McGill University, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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21
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Cho K. Neutrophil-Mediated Progression of Mild Cognitive Impairment to Dementia. Int J Mol Sci 2023; 24:14795. [PMID: 37834242 PMCID: PMC10572848 DOI: 10.3390/ijms241914795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 09/26/2023] [Accepted: 09/29/2023] [Indexed: 10/15/2023] Open
Abstract
Cognitive impairment is a serious condition that begins with amnesia and progresses to cognitive decline, behavioral dysfunction, and neuropsychiatric impairment. In the final stage, dysphagia and incontinence occur. There are numerous studies and developed drugs for cognitive dysfunction in neurodegenerative diseases, such as Alzheimer's disease (AD); however, their clinical effectiveness remains equivocal. To date, attempts have been made to overcome cognitive dysfunction and understand and delay the aging processes that lead to degenerative and chronic diseases. Cognitive dysfunction is involved in aging and the disruption of inflammation and innate immunity. Recent reports have indicated that the innate immune system is prevalent in patients with AD, and that peripheral neutrophil markers can predict a decline in executive function in patients with mild cognitive impairment (MCI). Furthermore, altered levels of pro-inflammatory interleukins have been reported in MCI, which have been suggested to play a role in the peripheral immune system during the process from early MCI to dementia. Neutrophils are the first responders of the innate immune system. Neutrophils eliminate harmful cellular debris via phagocytosis, secrete inflammatory factors to activate host defense systems, stimulate cytokine production, kill pathogens, and regulate extracellular proteases and inhibitors. This review investigated and summarized the regulation of neutrophil function during cognitive impairment caused by various degenerative diseases. In addition, this work elucidates the cellular mechanism of neutrophils in cognitive impairment and what is currently known about the effects of activated neutrophils on cognitive decline.
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Affiliation(s)
- KyoungJoo Cho
- Department of Life Science, Kyonggi University, Suwon 16227, Republic of Korea
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22
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Liaptsi E, Merkouris E, Polatidou E, Tsiptsios D, Gkantzios A, Kokkotis C, Petridis F, Christidi F, Karatzetzou S, Karaoglanis C, Tsagkalidi AM, Chouliaras N, Tsamakis K, Protopapa M, Pantazis-Pergaminelis D, Skendros P, Aggelousis N, Vadikolias K. Targeting Neutrophil Extracellular Traps for Stroke Prognosis: A Promising Path. Neurol Int 2023; 15:1212-1226. [PMID: 37873833 PMCID: PMC10594510 DOI: 10.3390/neurolint15040076] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/15/2023] [Accepted: 09/19/2023] [Indexed: 10/25/2023] Open
Abstract
Stroke has become the first cause of functional disability and one of the leading causes of mortality worldwide. Therefore, it is of crucial importance to develop accurate biomarkers to assess stroke risk and prognosis. Emerging evidence suggests that neutrophil extracellular trap (NET) levels may serve as a valuable biomarker to predict stroke occurrence and functional outcome. NETs are known to create a procoagulant state by serving as a scaffold for tissue factor (TF) and platelets inducing thrombosis by activating coagulation pathways and endothelium. A literature search was conducted in two databases (MEDLINE and Scopus) to trace all relevant studies published between 1 January 2016 and 31 December 2022, addressing the potential utility of NETs as a stroke biomarker. Only full-text articles in English were included. The current review includes thirty-three papers. Elevated NET levels in plasma and thrombi seem to be associated with increased mortality and worse functional outcomes in stroke, with all acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage included. Additionally, higher NET levels seem to correlate with worse outcomes after recanalization therapies and are more frequently found in strokes of cardioembolic or cryptogenic origin. Additionally, total neutrophil count in plasma seems also to correlate with stroke severity. Overall, NETs may be a promising predictive tool to assess stroke severity, functional outcome, and response to recanalization therapies.
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Affiliation(s)
- Eirini Liaptsi
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Ermis Merkouris
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Efthymia Polatidou
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Dimitrios Tsiptsios
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Aimilios Gkantzios
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Christos Kokkotis
- Department of Physical Education and Sport Science, Democritus University of Thrace, 69100 Komotini, Greece; (C.K.); (M.P.); (D.P.-P.); (N.A.)
| | - Foivos Petridis
- Third Department of Neurology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Foteini Christidi
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Stella Karatzetzou
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Christos Karaoglanis
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Anna-Maria Tsagkalidi
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Nikolaos Chouliaras
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
| | - Konstantinos Tsamakis
- King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK;
| | - Maria Protopapa
- Department of Physical Education and Sport Science, Democritus University of Thrace, 69100 Komotini, Greece; (C.K.); (M.P.); (D.P.-P.); (N.A.)
| | - Dimitrios Pantazis-Pergaminelis
- Department of Physical Education and Sport Science, Democritus University of Thrace, 69100 Komotini, Greece; (C.K.); (M.P.); (D.P.-P.); (N.A.)
| | - Panagiotis Skendros
- First Department of Internal Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Nikolaos Aggelousis
- Department of Physical Education and Sport Science, Democritus University of Thrace, 69100 Komotini, Greece; (C.K.); (M.P.); (D.P.-P.); (N.A.)
| | - Konstantinos Vadikolias
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.L.); (E.M.); (E.P.); (A.G.); (F.C.); (S.K.); (C.K.); (A.-M.T.); (N.C.); (K.V.)
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23
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Chou ML, Babamale AO, Walker TL, Cognasse F, Blum D, Burnouf T. Blood-brain crosstalk: the roles of neutrophils, platelets, and neutrophil extracellular traps in neuropathologies. Trends Neurosci 2023; 46:764-779. [PMID: 37500363 DOI: 10.1016/j.tins.2023.06.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/17/2023] [Accepted: 06/29/2023] [Indexed: 07/29/2023]
Abstract
Systemic inflammation, neurovascular dysfunction, and coagulopathy often occur concurrently in neuropathologies. Neutrophils and platelets have crucial synergistic roles in thromboinflammation and are increasingly suspected as effector cells contributing to the pathogenesis of neuroinflammatory diseases. In this review, we summarize the roles of platelet-neutrophil interactions in triggering complex pathophysiological events affecting the brain that may lead to the disruption of brain barriers, infiltration of toxic factors into the parenchyma, and amplification of neuroinflammation through the formation of neutrophil extracellular traps (NETs). We highlight the clinical significance of thromboinflammation in neurological disorders and examine the contributions of damage-associated molecular patterns (DAMPs) derived from platelets and neutrophils. These DAMPs originate from both infectious and non-infectious risk factors and contribute to the activation of inflammasomes during brain disorders. Finally, we identify knowledge gaps in the molecular mechanisms underlying neurodegenerative disease pathogenesis and emphasize the potential of interventions targeting platelets and neutrophils to treat neuroinflammatory diseases.
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Affiliation(s)
- Ming-Li Chou
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, New Taipei City 23561, Taiwan; INSERM UMRS 938, Centre de Recherche Saint-Antoine, Immune System and Neuroinflammation Laboratory, Hôpital Saint-Antoine, Paris 75012, France
| | - Abdulkareem Olarewaju Babamale
- Taiwan International Graduate Program in Molecular Medicine, Academia Sinica, Taipei 11266, Taiwan; Department of Zoology, Faculty of Life Sciences, University of Ilorin, Ilorin 240003, Nigeria
| | - Tara L Walker
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Fabrice Cognasse
- Etablissement Français du Sang Auvergne-Rhône-Alpes, 42023 Saint-Étienne, France; University Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 Sainbiose, 42023 Saint-Etienne, France
| | - David Blum
- University of Lille, INSERM, CHU Lille, UMR-S1172 LilNCog, Lille Neuroscience and Cognition, F-59000 Lille, France; Alzheimer & Tauopathies, LabEx DISTALZ, LiCEND, Lille F-59000, France; NeuroTMULille International Laboratory, University of Lille, F-59000 Lille, France
| | - Thierry Burnouf
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, New Taipei City 23561, Taiwan; International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, New Taipei City 23561, Taiwan; NeuroTMULille International Laboratory, Taipei Medical University, Taipei 10031, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei 11031, Taiwan; Brain and Consciousness Research Centre, Taipei Medical University Shuang Ho Hospital, New Taipei City 23561, Taiwan.
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24
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Yu M, Xiao G, Han L, Peng L, Wang H, He S, Lyu M, Zhu Y. QiShen YiQi and its components attenuate acute thromboembolic stroke and carotid thrombosis by inhibition of CD62P/PSGL-1-mediated platelet-leukocyte aggregate formation. Biomed Pharmacother 2023; 160:114323. [PMID: 36738500 DOI: 10.1016/j.biopha.2023.114323] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND QiShen YiQi (QSYQ) dropping pill, a component-based Chinese medicine consisting of benefiting Qi (YQ) and activating blood (HX) components, has been reported to exert a beneficial effect on cerebral ischemia-induced stroke. However, its efficacy and pharmacological mechanism on acute thromboembolic stroke is not clear. PURPOSE This study is to explore the preventative effect and pharmacological mechanism of QSYQ and its YQ/HX components on the formation of platelet-leukocyte aggregation (PLA) in acute thromboembolic stroke. STUDY DESIGN AND METHODS In vivo thromboembolic stroke model and FeCl3-induced carotid arterial occlusion models were used. Immunohistochemistry, Western blot, RT-qPCR, and flow cytometry experiments were performed to reveal the pharmacological mechanisms of QSYQ and its YQ/HX components. RESULTS In thromboembolic stroke rats, QSYQ significantly attenuated infarct area, improved neurological recovery, reduced PLA formation, and inhibited P-selection (CD62P)/ P-selectin glycoprotein ligand-1 (PSGL-1) expressions. The YQ component preferentially down-regulated PSGL-1 expression in leukocyte, while the HX component preferentially down-regulated CD62P expression in platelet. In carotid arterial thrombosis mice, QSYQ and its YQ/HX components inhibited thrombus formation, prolonged vessel occlusion time, reduced circulating leukocytes and P-selectin expression. PLA formation and platelet/leukocyte adhesion to endothelial cell were also inhibited by QSYQ and its YQ/HX components in vitro. CONCLUSION QSYQ and YQ/HX components attenuated thromboembolic stroke and carotid thrombosis by decreasing PLA formation via inhibiting CD62P/PSGL-1 expressions. This study shed a new light on the prevention of thromboembolic stroke.
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Affiliation(s)
- Mingxing Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China
| | - Guangxu Xiao
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China
| | - Linhong Han
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China
| | - Li Peng
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China
| | - Huanyi Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China
| | - Shuang He
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China
| | - Ming Lyu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China.
| | - Yan Zhu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China.
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25
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Jin J, Wang F, Tian J, Zhao X, Dong J, Wang N, Liu Z, Zhao H, Li W, Mang G, Hu S. Neutrophil extracellular traps contribute to coagulopathy after traumatic brain injury. JCI Insight 2023; 8:141110. [PMID: 36802340 PMCID: PMC10070118 DOI: 10.1172/jci.insight.141110] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 02/17/2023] [Indexed: 02/23/2023] Open
Abstract
Coagulopathy contributes to the majority of deaths and disabilities associated with traumatic brain injury (TBI). Whether neutrophil extracellular traps (NETs) contribute to an abnormal coagulation state in the acute phase of TBI remains unknown. Our objectives were to demonstrate the definitive role of NETs in coagulopathy in TBI. We detected NET markers in 128 TBI patients and 34 healthy individuals. Neutrophil-platelet aggregates were detected in blood samples from TBI patients and healthy individuals using flow cytometry and staining for CD41 and CD66b. Endothelial cells were incubated with isolated NETs and we detected the expression of vascular endothelial cadherin, syndecan-1, thrombomodulin, von Willebrand factor, phosphatidylserine, and tissue factor. In addition, we established a TBI mouse model to determine the potential role of NETs in TBI-associated coagulopathy. NET generation was mediated by high mobility group box 1 (HMGB1) from activated platelets and contributed to procoagulant activity in TBI. Furthermore, coculture experiments indicated that NETs damaged the endothelial barrier and caused these cells to assume a procoagulant phenotype. Moreover, the administration of DNase I before or after brain trauma markedly reduced coagulopathy and improved the survival and clinical outcome of mice with TBI.
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Affiliation(s)
- Jiaqi Jin
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fang Wang
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiawei Tian
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinyi Zhao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiawei Dong
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Nan Wang
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhihui Liu
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongtao Zhao
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenqiang Li
- Department of Vascular Surgery, Jinshan Hospital of Fudan University, Shanghai, China
| | - Ge Mang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shaoshan Hu
- Department of Neurosurgery, Cancer Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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26
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Association of platelet-to-neutrophil ratios with 1-year outcome and mortality in patients with acute ischemic stroke. Neurosci Lett 2023; 798:137016. [PMID: 36529389 DOI: 10.1016/j.neulet.2022.137016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 12/06/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND Platelet-neutrophil crosstalk is being increasingly recognized as a driver of inflammation and thrombosis in patients with ischemic stroke. The aim of this study was to investigate the potential of PNR value in predicting the long-term prognosis and evaluate whether or not an available and routine blood cell biomarker could help predict the long-term neurological function and mortality in AIS patients. METHODS A total of 718 patients with suspected acute ischemic stroke were involved and followed up for 1 year by standard telephone interview or reexamination. Kaplan-Meier curve, Univariate and Multivariate Cox Regression were analyzed using Statistical Packages for Social Sciences. RESULTS ROC curve for PNR to evaluate 1-year outcomes was analyzed and the area under the curve (AUC) was 0.659 (P < 0.001). The cutoff point was observed at 38.30, with a sensitivity of 53.09 % and a specificity of 71.25 %. Moreover, patients in PNR ≤ 38.30 were more likely to have more serious NIHSS on admission, 1-year mRS and higher 1-year mortality (P < 0.001, respectively). The 1-year mortality in the low PNR group was significantly higher than that of the high PNR group (log-rank tests: P < 0.0001). Age, NIHSS, RBC and PNR were combined into model B which significantly increased the AUC value from 0.736 to 0.888 compared to model A (including Age, NIHSS and RBC). CONCLUSION PNR may serve as a readily assessable biomarker for early predicting neurological deterioration and the long-term prognosis of AIS. The nomogram that included age, NIHSS, PNR and RBC may be a useful predictive tool for 1-year mortality.
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Zhao X, Han J, Zhou L, Zhao J, Huang M, Wang Y, Kou J, Kou Y, Jin J. High mobility group box 1 derived mainly from platelet microparticles exacerbates microvascular obstruction in no reflow. Thromb Res 2023; 222:49-62. [PMID: 36566704 DOI: 10.1016/j.thromres.2022.12.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
INTRODUCTION No reflow manifests coronary microvascular injury caused by continuous severe myocardial ischemia and reperfusion. Microvascular obstruction (MVO) has emerged as one fundamental mechanism of no reflow. However, the underlying pathophysiology remains incompletely defined. Herein, we explore the contribution of high mobility group box 1 (HMGB1), derived mainly from platelet microparticles exacerbating MVO in no reflow. MATERIALS AND METHODS 44 STEMI patients undergoing successful primary percutaneous coronary intervention (PCI) were included in our study. Plasma HMGB1 levels in both the peripheral artery (PA) and infarct-related coronary artery (IRA) were measured by ELISA. Flow cytometry and confocal microscopy assessed the level of HMGB1+ platelet derived microparticles (PMPs) and platelet activation. Flow cytometry and western blot evaluated the procoagulant activity (PCA) and the release of inflammatory factors of human microvascular endothelial cells (HCEMCs). RESULTS HMGB1 levels were significantly higher in the IRA in no-reflow patients. The levels of HMGB1+ PMPs were considerably higher in the IRA of patients with no reflow and were strongly associated with platelet activation. Moreover, our results show that HMGB1 interacts with human microvascular endothelial cells primarily through TLR4, inducing HCMEC proinflammatory, procoagulant phenotype, and monocyte recruitment, accelerating microvascular obstruction and facilitating the development of no reflow. CONCLUSION Our results illustrate a novel mechanism by which HMGB1, derived mainly from PMPs, plays a crucial role in the pathogenesis of no-reflow, revealing a novel therapeutic target.
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Affiliation(s)
- Xinyi Zhao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
| | - Jianbin Han
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
| | - Lijin Zhou
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinjin Zhao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
| | - Meijiao Huang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
| | - Yueqing Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China
| | - Junjie Kou
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China.
| | - Yan Kou
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China.
| | - Jiaqi Jin
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Heilongjiang Province, Harbin, China; Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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28
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Sun S, Zou X, Wang D, Liu Y, Zhang Z, Guo J, Lu R, Huang W, Wang S, Li Z, Tian J, Yu H, Fu J, Fang S. IRGM/Irgm1 deficiency inhibits neutrophil-platelet interactions and thrombosis in experimental atherosclerosis and arterial injury. Biomed Pharmacother 2023; 158:114152. [PMID: 36580725 DOI: 10.1016/j.biopha.2022.114152] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/15/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Neutrophil extracellular traps (NETs) closely link inflammation and thrombosis. The immune-related GTPase family M protein (IRGM) and its ortholog of mouse IRGM1 are positively correlated with plaque rupture during atherosclerosis process. However, whether and how IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis remains unknown, which will further promote the development of antithrombotic treatment tools. METHODS The thrombi images, platelet activation makers and NETs makers were detected in the serum of STEMI patients and controls. To futher investigate IRGM/IRGM1 affects NETs formation and atherothrombosis in vivo, ApoE-/-Irgm1+/- and ApoE-/- mice received diets rich in fat and 2.5% FeCl3 was then used to induce experimental arterial thrombosis in an atherosclerosis background. In vitro, PMA and thrombin were used to stimulate neutrophils and platelets, respectively, and the expression of IRGM/IRGM1 were modified. To reveal the molecular mechanisms, MAPK-cPLA2 signals inhibitors were used. RESULTS Serum IRGM was positively correlated with PF4 and neutrophil elastase. Subsequently, Irgm1 deficient mice have a longer occlusion time and lower growth rate. In vitro, as expected, IRGM/Irgm1 deficiency inhibits platelet activation and platelet-neutrophil interaction. More importantly, IRGM promoted NETs production through activating MAPK-cPLA2 signals in PMA stimulated neuropils, whereas inhibiting the production of NETs eliminated the difference in platelet activation and thrombosis caused by IRGM/Irgm1 modification in vivo and vitro. Similarly, inhibition of platelet activation also eliminated the influence of IRGM/Irgm1 modification on NETs production. CONCLUSIONS Overall, our data indicate that IRGM/Irgm1 deficiency in neuropils inhibits the intense interaction between neutrophils and platelets, and ultimately inhibits thrombosis.
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Affiliation(s)
- Song Sun
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Xiaoyi Zou
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Duo Wang
- Department of Neurology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yige Liu
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Zhenming Zhang
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Junchen Guo
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Rongzhe Lu
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Wei Huang
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Shanjie Wang
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Zhaoying Li
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Jiangtian Tian
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Huai Yu
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
| | - Jin Fu
- Department of Neurology, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Shaohong Fang
- Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China.
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Platelet-Neutrophil Crosstalk in Thrombosis. Int J Mol Sci 2023; 24:ijms24021266. [PMID: 36674781 PMCID: PMC9861587 DOI: 10.3390/ijms24021266] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/02/2023] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Platelets are essential for the formation of a haemostatic plug to prevent bleeding, while neutrophils are the guardians of our immune defences against invading pathogens. The interplay between platelets and innate immunity, and subsequent triggering of the activation of coagulation is part of the host system to prevent systemic spread of pathogen in the blood stream. Aberrant immunothrombosis and excessive inflammation can however, contribute to the thrombotic burden observed in many cardiovascular diseases. In this review, we highlight how platelets and neutrophils interact with each other and how their crosstalk is central to both arterial and venous thrombosis and in COVID-19. While targeting platelets and coagulation enables efficient antithrombotic treatments, they are often accompanied with a bleeding risk. We also discuss how novel approaches to reduce platelet-mediated recruitment of neutrophils could represent promising therapies to treat thrombosis without affecting haemostasis.
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Zhao Z, Pan Z, Zhang S, Ma G, Zhang W, Song J, Wang Y, Kong L, Du G. Neutrophil extracellular traps: A novel target for the treatment of stroke. Pharmacol Ther 2023; 241:108328. [PMID: 36481433 DOI: 10.1016/j.pharmthera.2022.108328] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/30/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
Stroke is a threatening cerebrovascular disease caused by thrombus with high morbidity and mortality rates. Neutrophils are the first to be recruited in the brain after stroke, which aggravate brain injury through multiple mechanisms. Neutrophil extracellular traps (NETs), as a novel regulatory mechanism of neutrophils, can trap bacteria and secret antimicrobial molecules, thereby degrading pathogenic factors and killing bacteria. However, NETs also exacerbate certain non-infectious diseases by activating autoimmune or inflammatory responses. NETs have been found to play important roles in the pathological process of stroke in recent years. In this review, the mechanisms of NETs formation, the physiological roles of NETs, and the dynamic changes of NETs after stroke are summarized. NETs participate in stroke through various mechanisms. NETs promote the coagulation cascade and interact with platelets to induce thrombosis. tPA induces the degranulation of neutrophils to form NETs, leading to hemorrhagic transformation and thrombolytic resistance. NETs aggravate stroke by mediating inflammation, atherosclerosis and vascular injury. In addition, the regulation of NETs in stroke, the potential of NETs as biomarker and the treatment of stroke targeting NETs are discussed. The increasing evidences suggest that NETs may be a potential target for stroke treatment. Inhibition of NETs formation or promotion of NETs degradation plays protective effects in stroke. However, how to avoid the adverse effects of NETs-targeted therapy deserves further study. In summary, this review provides a reference for the pathogenesis, drug targets, biomarkers and drug development of NETs in stroke.
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Affiliation(s)
- Ziyuan Zhao
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Zirong Pan
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Sen Zhang
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Guodong Ma
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Wen Zhang
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Junke Song
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Yuehua Wang
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Linglei Kong
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
| | - Guanhua Du
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
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Luo H, Guo H, Zhou Y, Fang R, Zhang W, Mei Z. Neutrophil Extracellular Traps in Cerebral Ischemia/Reperfusion Injury: Friend and Foe. Curr Neuropharmacol 2023; 21:2079-2096. [PMID: 36892020 PMCID: PMC10556361 DOI: 10.2174/1570159x21666230308090351] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/19/2022] [Accepted: 12/26/2022] [Indexed: 03/10/2023] Open
Abstract
Cerebral ischemic injury, one of the leading causes of morbidity and mortality worldwide, triggers various central nervous system (CNS) diseases, including acute ischemic stroke (AIS) and chronic ischemia-induced Alzheimer's disease (AD). Currently, targeted therapies are urgently needed to address neurological disorders caused by cerebral ischemia/reperfusion injury (CI/RI), and the emergence of neutrophil extracellular traps (NETs) may be able to relieve the pressure. Neutrophils are precursors to brain injury following ischemic stroke and exert complicated functions. NETs extracellularly release reticular complexes of neutrophils, i.e., double-stranded DNA (dsDNA), histones, and granulins. Paradoxically, NETs play a dual role, friend and foe, under different conditions, for example, physiological circumstances, infection, neurodegeneration, and ischemia/reperfusion. Increasing evidence indicates that NETs exert anti-inflammatory effects by degrading cytokines and chemokines through protease at a relatively stable and moderate level under physiological conditions, while excessive amounts of NETs release (NETosis) irritated by CI/RI exacerbate the inflammatory response and aggravate thrombosis, disrupt the blood-brain barrier (BBB), and initiates sequential neuron injury and tissue damage. This review provides a comprehensive overview of the machinery of NETs formation and the role of an abnormal cascade of NETs in CI/RI, as well as other ischemia-induced neurological diseases. Herein, we highlight the potential of NETs as a therapeutic target against ischemic stroke that may inspire translational research and innovative clinical approaches.
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Affiliation(s)
- Haoyue Luo
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Hanjing Guo
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Yue Zhou
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Rui Fang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Wenli Zhang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Zhigang Mei
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
- Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, Medical College of China Three Gorges University, Yichang, Hubei, 443002, China
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Qiao S, Sun QY, Zhou P, Zhang SC, Wang ZH, Li HY, Wang AH, Liu XW, Xin T. Increased formation of neutrophil extracellular traps in patients with anti-N-methyl-d-aspartate receptor encephalitis. Front Immunol 2022; 13:1046778. [PMID: 36569875 PMCID: PMC9780054 DOI: 10.3389/fimmu.2022.1046778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/15/2022] [Indexed: 12/13/2022] Open
Abstract
Background Neutrophil extracellular traps (NETs) have been found to play an important role in several nervous system diseases. However, their role in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remains unclear. The purpose of this study was to examine the possible role of NETs in anti-NMDAR encephalitis. Materials and methods Eleven patients with anti-NMDAR encephalitis and ten healthy participants were enrolled. Plasma NETs levels were detected using an immunofluorescence assay and enzyme-linked immunosorbent assay. Additionally, we examined 10 plasma cytokines in patients with anti-NMDAR encephalitis and analyzed the correlation between citrullinated histone 3 levels and cytokine release. Results Peripheral blood neutrophils from patients with anti-NMDAR encephalitis were more susceptible to NET generation. When compared with controls, cases of anti-NMDAR encephalitis showed elevated levels of IL-1 α, IL-6, IL-8, IL-13, MCP-1, and TNF-α (p < 0.05). Moreover, IL-6, IL-8, and TNF-α levels were positively correlated with H3Cit levels. Conclusion We provide evidence that NETs may play a role in anti-NMDAR encephalitis, providing clues for elucidation of the pathogenesis of this disease.
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Affiliation(s)
- Shan Qiao
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Quan-ye Sun
- Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Peng Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Shan-chao Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China,School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhi-hao Wang
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, China
| | - Hai-yun Li
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, China
| | - Ai-hua Wang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Xue-wu Liu
- Department of Neurology, Qilu Hospital of Shandong University, Jinan, China,Institute of Epilepsy, Shandong University, Jinan, China,*Correspondence: Tao Xin, ; Xue-wu Liu,
| | - Tao Xin
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China,*Correspondence: Tao Xin, ; Xue-wu Liu,
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Jin J, Qiao S, Liu J, Li W, Wang F, Gao X, Tian J, Wang N, Zhang J, Dong J, li H, Wang J, Hu S, Zhou P. Neutrophil extracellular traps promote thrombogenicity in cerebral venous sinus thrombosis. Cell Biosci 2022; 12:114. [PMID: 35869501 PMCID: PMC9306243 DOI: 10.1186/s13578-022-00845-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/06/2022] [Indexed: 11/17/2022] Open
Abstract
Background Neutrophil extracellular traps (NETs) contribute to the creation of a coagulation state in various diseases. Currently, it is not clear whether NETs are present in the thrombi and plasma of patients with cerebral venous sinus thrombosis (CVST). This study aimed to investigate the presence of NETs in thrombi and blood samples from CVST patients and the procoagulant activity (PCA) of NETs during the progression of CVST. Results Thrombi obtained from CVST patients undergoing thrombectomy were examined by immunochemistry using neutrophil elastase (NE), CD66b and citrullinated histone H3(citH3). The presence of NET markers in samples from 37 CVST patients and 32 healthy people was evaluated by ELISA. NET-producing neutrophils and neutrophil-platelet (PLT) aggregates were examined in samples obtained from CVST patients and healthy people by flow cytometry. The TAT complex in plasma sample from each group was detected by ELISA to evaluate the procoagulant activity of NETs in CVST patients. Neutrophils from healthy subjects were treated with PLT-rich plasma in the presence of anti-PF4 antibodies or an autophagy inhibitor and analyzed by flow cytometry and confocal microscopy. After treatment with NETs, the expression of von Willebrand factor (VWF), tissue factor (TF) and CD31 in human brain microvascular endothelial cells (HBMECs) was measured by confocal microscopy and western blotting. Our results showed that NETs were abundant in the plasma and thrombi from CVST patients. Platelet factor 4 (PF4) from CVST PLTs induced NET generation through autophagy. NETs could induce PCA by modulating TF and phosphatidylserine (PS) in CVST. NETs also disrupted the endothelial barrier and transformed ECs into a procoagulant phenotype to exacerbate thrombogenicity. Conclusions NET generation was mediated by PF4 from PLTs through autophagy and contribute to thrombosis in CVST patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00845-z.
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He Y, Wu Q. The Effect of Extracellular Vesicles on Thrombosis. J Cardiovasc Transl Res 2022:10.1007/s12265-022-10342-w. [DOI: 10.1007/s12265-022-10342-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/17/2022] [Indexed: 11/29/2022]
Abstract
Abstract
The risk of cardiovascular events caused by acute thrombosis is high, including acute myocardial infarction, acute stroke, acute pulmonary embolism, and deep vein thrombosis. In this review, we summarize the roles of extracellular vesicles of different cellular origins in various cardiovascular events associated with acute thrombosis, as described in the current literature, to facilitate the future development of a precise therapy for thrombosis caused by such vesicles. We hope that our review will indicate a new horizon in the field of cardiovascular research with regard to the treatment of acute thrombosis, especially targeting thrombosis caused by extracellular vesicles secreted by individual cells. As more emerging technologies are being developed, new diagnostic and therapeutic strategies related to EVs are expected to be identified for related diseases in the future.
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Investigation of Neutrophil Extracellular Traps as Potential Mediators in the Pathogenesis of Non-Acute Subdural Hematomas: A Pilot Study. Diagnostics (Basel) 2022; 12:diagnostics12122934. [PMID: 36552941 PMCID: PMC9776444 DOI: 10.3390/diagnostics12122934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Non-acute subdural hematomas (NASHs) are a cause of significant morbidity and mortality, particularly with recurrences. Although recurrence is believed to involve a disordered neuroinflammatory cascade involving vascular endothelial growth factor (VEGF), this pathway has yet to be completely elucidated. Neutrophil extracellular traps (NETs) are key factors that promote inflammation/apoptosis and can be induced by VEGF. We investigated whether NETs are present in NASH membranes, quantified NET concentrations, and examined whether NET and VEGF levels are correlated in NASHs. Samples from patients undergoing NASH evacuation were collected during surgery and postoperatively at 24 and 48 h. Fluid samples and NASH membranes were analyzed for levels of VEGF, NETs, and platelet activation. NASH samples contained numerous neutrophils positive for NET formation. Myeloperoxidase-DNA complexes (a marker of NETs) remained elevated 48 h postoperatively (1.06 ± 0.22 day 0, 0.72 ± 0.23 day 1, and 0.83 ± 0.33 day 2). VEGF was also elevated in NASHs (7.08 ± 0.98 ng/mL day 0, 3.40 ± 0.68 ng/mL day 1, and 6.05 ± 1.8 ng/mL day 2). VEGF levels were significantly correlated with myeloperoxidase-DNA levels. These results show that NETs are increasing in NASH, a finding that was previously unknown. The strong correlation between NET and VEGF levels indicates that VEGF may be an important mediator of NET-related inflammation in NASH.
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Recent Insights into Neutrophil Extracellular Traps in Cardiovascular Diseases. J Clin Med 2022; 11:jcm11226662. [PMID: 36431139 PMCID: PMC9698501 DOI: 10.3390/jcm11226662] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022] Open
Abstract
Neutrophils are primary effector cells of the innate immune system. Emerging evidence has consistently shown that activated neutrophils produce and release neutrophil extracellular traps (NETs) that play roles in immunity and non-infectious diseases. NETs are composed of DNA and proteins and serve as a structural platform for pathogen sequestration and degradation. In contrast to their protective role during pathogenic infection, NETs are pathologically involved in cardiovascular disease (CVD). In this review, we introduce the formation, release, and clearance of NETs and the regulatory mechanisms of NETs formation, followed by an overview of the clinical evidence for the involvement of NETs in CVD. Because atherosclerosis is a fundamental part of the pathogenesis of CVD, we chose to focus on the mechanisms by which NETs promote endothelial cell damage and collaborate with macrophages and platelets to accelerate plaque progression and thrombosis. Finally, we present options for clinical intervention to inhibit NETs production and release in the treatment of CVD. In conclusion, this review integrates the latest findings and provides new insights into NETs, which represent a novel biomarker and therapeutic target in clinical practice.
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Li J, Tong D, Song B, Xie F, Zhang G, Hao X, Li W, Chi H, Wang W, Shao Y. Inflammatory cytokines induce neutrophil extracellular traps interaction with activated platelets and endothelial cells exacerbate coagulation in moderate and severe essential hypertension. J Hypertens 2022; 40:2219-2229. [PMID: 35950987 DOI: 10.1097/hjh.0000000000003250] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Essential hypertension (EH) patients suffer from paradoxically thrombotic rather than haemorrhagic, although the exact mechanism remains elusive. Our aim is to explore whether and how neutrophil extracellular traps (NETs) play the procoagulant role in EH patients, as well as evaluated whether the NET releasing were triggered by inflammatory cytokines. METHODS The concentration of plasma NETs components were detected by ELISA. The morphology of cells and NETs formation were analysed using immunofluorescence. Procoagulant activity was analysed by clotting time, purified coagulation complex and fibrin generation assays. Phosphatidylserine (PS) exposure on endothelial cells (ECs) was analysed with flow cytometry. RESULTS Moderate to severe EH patients plasma NETs levels were significantly higher compared to mild EH patients or controls. Furthermore, inflammatory cytokines can induce NETs generation, depleting these patients plasma inflammatory cytokines led to a reduction in NET releasing. NETs from moderate to severe EH patients neutrophils led to significantly decreased clotting time (CT), increased potency to generate thrombin and fibrin (all P < 0.05). These procoagulant effects were markedly attenuated by approximately 70% using DNase I. Additionally, high concentrations NETs exerted a strong cytotoxic effect on ECs, conferring them a procoagulant phenotype. CONCLUSION Our study reveals that EH drives a systemic inflammatory environment, which, in turn, drives neutrophils to prime and NET releasing, and found a link between hypercoagulability and NETs levels in moderate to severe EH patients. Therefore, anti-inflammatory combined with block the generation of NETs may represent a new therapeutic target for preventing thrombosis in EH patients.
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Affiliation(s)
- Jihe Li
- Department of Cardiology
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, Heilongjiang Province, China
| | - Dongxia Tong
- Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao
| | - Bin Song
- Department of Geriatrics, Second Hospital of Traditional Chinese Medicine, Tai'an
| | | | - Guixin Zhang
- Department of General Surgery, Qingdao FUWAI Cardiovascular Hospital, Qingdao
| | - Xin Hao
- Department of Ophthalmology, Second Hospital of Traditional Chinese Medicine, Tai'an, Shandong Province
| | | | | | - Weiming Wang
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, Heilongjiang Province, China
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Schoen J, Euler M, Schauer C, Schett G, Herrmann M, Knopf J, Yaykasli KO. Neutrophils' Extracellular Trap Mechanisms: From Physiology to Pathology. Int J Mol Sci 2022; 23:12855. [PMID: 36361646 PMCID: PMC9653572 DOI: 10.3390/ijms232112855] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 07/30/2023] Open
Abstract
Neutrophils are an essential part of the innate immune system and the first line of defense against invading pathogens. They phagocytose, release granular contents, produce reactive oxygen species, and form neutrophil extracellular traps (NETs) to fight pathogens. With the characterization of NETs and their components, neutrophils were identified as players of the innate adaptive crosstalk. This has placed NETs at the center not only of physiological but also pathological processes. Aside from their role in pathogen uptake and clearance, NETs have been demonstrated to contribute to the resolution of inflammation by forming aggregated NETs able to degrade inflammatory mediators. On the other hand, NETs have the potential to foster severe pathological conditions. When homeostasis is disrupted, they occlude vessels and ducts, serve as sources of autoantigens and danger or damage associated molecular patterns, directly damage tissues, and exaggerate complement activity and inflammation. This review focusses on the understanding of NETs from their formation to their functions in both physiological and pathological processes.
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Affiliation(s)
- Janina Schoen
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Maximilien Euler
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Christine Schauer
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Martin Herrmann
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Jasmin Knopf
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Kursat Oguz Yaykasli
- Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
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Benramdane H, Nasri S, Ouahabi N, Belharti A, Chehita K, Yassine M, Housni B, Skiker I. Multiple ischemic stroke with pulmonary embolism revealing severe COVID-19 infection in a young healthy patient. Radiol Case Rep 2022; 17:4879-4884. [PMID: 36247700 PMCID: PMC9557746 DOI: 10.1016/j.radcr.2022.08.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/01/2022] [Accepted: 08/08/2022] [Indexed: 11/26/2022] Open
Abstract
Coronavirus 2019 (COVID-19) disease has caused significant morbidity and mortality worldwide since its emergence in December 2019. Despite its respiratory tropism; there is a nontrivial relationship between this virus and the neurovascular system exposing patients to higher morbidity and mortality. We report the case of a young patient admitted for hemiplegia with acute respiratory failure, in whom imaging found multiple ischemic strokes with pulmonary embolism and severe involvement suggestive of COVID-19 pneumopathy. Stroke in the context of COVID-19 infection has distinct characteristics in terms of disease mechanism, patient demographics, but also clinical, biological, and neuroradiological specificities. The pathogenesis and optimal management of COVID-19-associated ischemic stroke remain unclear, but the coagulopathy and endotheliopathy triggered by the cytokine storm represent possible target mechanisms.
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Affiliation(s)
- Hicham Benramdane
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco,Department of Radiology, Mohammed VI University Hospital Mohammed I University, Oujda, Morocco,Corresponding author.
| | - Siham Nasri
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco,Department of Radiology, Mohammed VI University Hospital Mohammed I University, Oujda, Morocco
| | - Nada Ouahabi
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco,Department of Anesthesiology and Intensive Care Unit, Mohammed VI University Hospital Mohammed I University, Oujda, Morocco
| | - Aahd Belharti
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco,Department of Radiology, Mohammed VI University Hospital Mohammed I University, Oujda, Morocco
| | - Kaouthar Chehita
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco,Department of Neurology, Mohammed VI University Hospital Mohammed I University, Oujda, Morocco
| | - Mebrouk Yassine
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco,Department of Neurology, Mohammed VI University Hospital Mohammed I University, Oujda, Morocco
| | - Brahim Housni
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco,Department of Anesthesiology and Intensive Care Unit, Mohammed VI University Hospital Mohammed I University, Oujda, Morocco
| | - Imane Skiker
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco,Department of Radiology, Mohammed VI University Hospital Mohammed I University, Oujda, Morocco
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40
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Ma S, Wang F, Dong J, Wang N, Tao S, Du J, Hu S. Inhibition of hypoxia-inducible factor 1 by acriflavine renders glioblastoma sensitive for photodynamic therapy. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2022; 234:112537. [PMID: 35939916 DOI: 10.1016/j.jphotobiol.2022.112537] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 07/11/2022] [Accepted: 07/29/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND photodynamics therapy (PDT) induces tumor cell death through oxidative stress and is closely associated with the expression of hypoxia inducible factor-1a (HIF1a), which activates multiple downstream survival signaling pathways. Therefore, the purpose of this study was to investigate the expression levels of HIF1a proteins in PDT-treated GBM cells and to determine whether inhibition of HIF1a reduces survival signals to enhance the efficacy of PDT. RESULTS PDT combined with Acriflavine (ACF, PA) decreased the expression of HIF1a and regulated the downstream expression of GLUT-1, GLUT-3, HK2 and other gluconeogenic pathway proteins. PA group significantly suppressed tumor growth to improve the efficacy of PDT. METHODS We first performed the correlation of HIF1a, GLUT-1, GLUT-3, and HK2, and quantified the expression of HIF1a on tumor grades and IDH mutation classification by TCGA and CGGA databases. Then, we used immunohistochemistry method to detect four gene expression levels in human GBM tissues. Besides, we examined the effects of different treatments on the proliferation, migration and invasion ability of GBM cell lines by CCK8, wound healing and transwell assays. ACF, a HIF1a/HIF1β dimerization inhibitor, was used to evaluate its adjuvant effect on the efficacy of PDT. CONCLUSION HIF1a is activated in GBM cell lines and contributes to the survival of tumor cells after PDT in vitro and in vivo. PA group inhibited HIF1a expression and improved PDT efficacy in the treatment of recalcitrant GBM.
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Affiliation(s)
- Shuai Ma
- Department of Neurosurgery, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450053, China; Department of Neurosurgery, Emergency Medicine Center, Zhejiang Provincial People's Hospital Affiliated to Hangzhou Medical College, Hangzhou, China; TranslationalMedicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Fang Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Jiawei Dong
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China; TranslationalMedicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Nan Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Shengzhong Tao
- Department of Neurosurgery, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450053, China.
| | - Jianyang Du
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
| | - Shaoshan Hu
- Department of Neurosurgery, Emergency Medicine Center, Zhejiang Provincial People's Hospital Affiliated to Hangzhou Medical College, Hangzhou, China; Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
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41
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Hu W, Lee SML, Bazhin AV, Guba M, Werner J, Nieß H. Neutrophil extracellular traps facilitate cancer metastasis: cellular mechanisms and therapeutic strategies. J Cancer Res Clin Oncol 2022; 149:2191-2210. [PMID: 36050539 PMCID: PMC9436160 DOI: 10.1007/s00432-022-04310-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/15/2022] [Indexed: 11/24/2022]
Abstract
Background The formation of neutrophil extracellular traps (NETs) was initially discovered as a novel immune response against pathogens. Recent studies have also suggested that NETs play an important role in tumor progression. This review summarizes the cellular mechanisms by which NETs promote distant metastasis and discusses the possible clinical applications targeting NETs. Method The relevant literature from PubMed and Google Scholar (2001–2021) have been reviewed for this article. Results The presence of NETs has been detected in various primary tumors and metastatic sites. NET-associated interactions have been observed throughout the different stages of metastasis, including initial tumor cell detachment, intravasation and extravasation, the survival of circulating tumor cells, the settlement and the growth of metastatic tumor cells. Several in vitro and in vivo studies proved that inhibiting NET formation resulted in anti-cancer effects. The biosafety and efficacy of some NET inhibitors have also been demonstrated in early phase clinical trials. Conclusions Considering the role of NETs in tumor progression, NETs could be a promising diagnostic and therapeutic target for cancer management. However, current evidence is mostly derived from experimental models and as such more clinical studies are still needed to verify the clinical significance of NETs in oncological settings.
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Affiliation(s)
- Wenxing Hu
- Department of General, Visceral, and Transplant Surgery, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Serene M L Lee
- Department of General, Visceral, and Transplant Surgery, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.,Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Hanno Nieß
- Department of General, Visceral, and Transplant Surgery, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany.
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42
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Han T, Tang H, Lin C, Shen Y, Yan D, Tang X, Guo D. Extracellular traps and the role in thrombosis. Front Cardiovasc Med 2022; 9:951670. [PMID: 36093130 PMCID: PMC9452724 DOI: 10.3389/fcvm.2022.951670] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
Thrombotic complications pose serious health risks worldwide. A significant change in our understanding of the pathophysiology of thrombosis has occurred since the discovery of extracellular traps (ETs) and their prothrombotic properties. As a result of immune cells decondensing chromatin into extracellular fibers, ETs promote thrombus formation by acting as a scaffold that activates platelets and coagulates them. The involvement of ETs in thrombosis has been reported in various thrombotic conditions including deep vein thrombosis (DVT), pulmonary emboli, acute myocardial infarction, aucte ischemic stroke, and abdominal aortic aneurysms. This review summarizes the existing evidence of ETs in human and animal model thrombi. The authors described studies showing the existence of ETs in venous or arterial thrombi. In addition, we studied potential novel therapeutic opportunities related to the resolution or prevention of thrombosis by targeting ETs.
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43
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Zhao J, Jin J. Neutrophil extracellular traps: New players in cancer research. Front Immunol 2022; 13:937565. [PMID: 36059520 PMCID: PMC9437524 DOI: 10.3389/fimmu.2022.937565] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
NETs are chromatin-derived webs extruded from neutrophils as a result of either infection or sterile stimulation using chemicals, cytokines, or microbes. In addition to the classical role that NETs play in innate immunity against infection and injuries, NETs have been implicated extensively in cancer progression, metastatic dissemination, and therapy resistance. The purpose of this review is to describe recent investigations into NETs and the roles they play in tumor biology and to explore their potential as therapeutic targets in cancer treatment.
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Affiliation(s)
- Junjie Zhao
- Department of General Surgery, Changsha Hospital Affiliated to Hunan Normal University/The Fourth Hospital of Changsha, Changsha, China
- *Correspondence: Junjie Zhao, ; Jiaqi Jin,
| | - Jiaqi Jin
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Junjie Zhao, ; Jiaqi Jin,
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44
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Jin J, Zhao X, Li W, Wang F, Tian J, Wang N, Gao X, Zhang J, Wu J, Mang G, Ma R, Hu S. Neutrophil extracellular traps: A novel therapeutic target for intracranial hemorrhage. Thromb Res 2022; 219:1-13. [DOI: 10.1016/j.thromres.2022.08.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 08/16/2022] [Accepted: 08/22/2022] [Indexed: 10/31/2022]
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45
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Wienkamp AK, Erpenbeck L, Rossaint J. Platelets in the NETworks interweaving inflammation and thrombosis. Front Immunol 2022; 13:953129. [PMID: 35979369 PMCID: PMC9376363 DOI: 10.3389/fimmu.2022.953129] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/07/2022] [Indexed: 12/18/2022] Open
Abstract
Platelets are well characterized for their indispensable role in primary hemostasis to control hemorrhage. Research over the past years has provided a substantial body of evidence demonstrating that platelets also participate in host innate immunity. The surface expression of pattern recognition receptors, such as TLR2 and TLR4, provides platelets with the ability to sense bacterial products in their environment. Platelet α-granules contain microbicidal proteins, chemokines and growth factors, which upon release may directly engage pathogens and/or contribute to inflammatory signaling. Additionally, platelet interactions with neutrophils enhance neutrophil activation and are often crucial to induce a sufficient immune response. In particular, platelets can activate neutrophils to form neutrophil extracellular traps (NETs). This specific neutrophil effector function is characterized by neutrophils expelling chromatin fibres decorated with histones and antimicrobial proteins into the extracellular space where they serve to trap and kill pathogens. Until now, the mechanisms and signaling pathways between platelets and neutrophils inducing NET formation are still not fully characterized. NETs were also detected in thrombotic lesions in several disease backgrounds, pointing towards a role as an interface between neutrophils, platelets and thrombosis, also known as immunothrombosis. The negatively charged DNA within NETs provides a procoagulant surface, and in particular NET-derived proteins may directly activate platelets. In light of the current COVID-19 pandemic, the topic of immunothrombosis has become more relevant than ever, as a majority of COVID-19 patients display thrombi in the lung capillaries and other vascular beds. Furthermore, NETs can be found in the lung and other tissues and are associated with an increased mortality. Here, virus infiltration may lead to a cytokine storm that potently activates neutrophils and leads to massive neutrophil infiltration into the lung and NET formation. The resulting NETs presumably activate platelets and coagulation factors, further contributing to the subsequent emergence of microthrombi in pulmonary capillaries. In this review, we will discuss the interplay between platelets and NETs and the potential of this alliance to influence the course of inflammatory diseases. A better understanding of the underlying molecular mechanisms and the identification of treatment targets is of utmost importance to increase patients’ survival and improve the clinical outcome.
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Affiliation(s)
- Ann-Katrin Wienkamp
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Luise Erpenbeck
- Department of Dermatology, University Hospital Münster, Münster, Germany
| | - Jan Rossaint
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
- *Correspondence: Jan Rossaint,
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46
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Matta B, Battaglia J, Barnes BJ. Detection of neutrophil extracellular traps in patient plasma: method development and validation in systemic lupus erythematosus and healthy donors that carry IRF5 genetic risk. Front Immunol 2022; 13:951254. [PMID: 35958624 PMCID: PMC9360330 DOI: 10.3389/fimmu.2022.951254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/04/2022] [Indexed: 01/21/2023] Open
Abstract
Neutrophil extracellular traps (NETs) are web-like structures extruded by neutrophils after activation or in response to microorganisms. These extracellular structures are decondensed chromatin fibers loaded with antimicrobial granular proteins, peptides, and enzymes. NETs clear microorganisms, thus keeping a check on infections at an early stage, but if dysregulated, may be self-destructive to the body. Indeed, NETs have been associated with autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), antiphospholipid syndrome (APS), psoriasis, and gout. More recently, increased NETs associate with COVID-19 disease severity. While there are rigorous and reliable methods to quantify NETs from neutrophils via flow cytometry and immunofluorescence, the accurate quantification of NETs in patient plasma or serum remains a challenge. Here, we developed new methodologies for the quantification of NETs in patient plasma using multiplex ELISA and immunofluorescence methodology. Plasma from patients with SLE, non-genotyped healthy controls, and genotyped healthy controls that carry either the homozygous risk or non-risk IRF5-SLE haplotype were used in this study. The multiplex ELISA using antibodies detecting myeloperoxidase (MPO), citrullinated histone H3 (CitH3) and DNA provided reliable detection of NETs in plasma samples from SLE patients and healthy donors that carry IRF5 genetic risk. An immunofluorescence smear assay that utilizes only 1 µl of patient plasma provided similar results and data correlate to multiplex ELISA findings. The immunofluorescence smear assay is a relatively simple, inexpensive, and quantifiable method of NET detection for small volumes of patient plasma.
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Affiliation(s)
- Bharati Matta
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Jenna Battaglia
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Betsy J. Barnes
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Molecular Medicine and Pediatrics, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- *Correspondence: Betsy J. Barnes,
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47
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Ogweno G. Challenges in Platelet Functions in HIV/AIDS Management. Infect Dis (Lond) 2022. [DOI: 10.5772/intechopen.105731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The interest in platelet functions in HIV/AIDS is due to the high incidence of microvascular thrombosis in these individuals. A lot of laboratory data have been generated regarding platelet functions in this population. The tests demonstrate platelet hyperactivity but decreased aggregation, though results are inconsistent depending on the study design. Antiretroviral treatments currently in use display complex interactions. Many studies on platelet functions in these patients have been for research purposes, but none have found utility in guiding drug treatment of thrombosis.
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48
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Schrader JM, Stanisavljevic A, Xu F, Van Nostrand WE. Distinct Brain Proteomic Signatures in Cerebral Small Vessel Disease Rat Models of Hypertension and Cerebral Amyloid Angiopathy. J Neuropathol Exp Neurol 2022; 81:731-745. [PMID: 35856898 PMCID: PMC9803909 DOI: 10.1093/jnen/nlac057] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Cerebral small vessel diseases (CSVDs) are prominent contributors to vascular cognitive impairment and dementia and can arise from a range of etiologies. Cerebral amyloid angiopathy (CAA) and hypertension (HTN), both prevalent in the elderly population, lead to cerebral microhemorrhages, macrohemorrhages, and white matter damage. However, their respective underlying mechanisms and molecular events are poorly understood. Here, we show that the transgenic rat model of CAA type 1 (rTg-DI) exhibits perivascular inflammation that is lacking in the spontaneously hypertensive stroke-prone (SHR-SP) rat model of HTN. Alternatively, SHR-SP rats display notable dilation of arteriolar perivascular spaces. Comparative proteomics analysis revealed few shared altered proteins, with key proteins such as ANXA3, H2A, and HTRA1 unique to rTg-DI rats, and Nt5e, Flot-1 and Flot-2 unique to SHR-SP rats. Immunolabeling confirmed that upregulation of ANXA3, HTRA1, and neutrophil extracellular trap proteins were distinctly associated with rTg-DI rats. Pathway analysis predicted activation of TGF-β1 and TNFα in rTg-DI rat brain, while insulin signaling was reduced in the SHR-SP rat brain. Thus, we report divergent protein signatures associated with distinct cerebral vessel pathologies in the SHR-SP and rTg-DI rat models and provide new mechanistic insight into these different forms of CSVD.
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Affiliation(s)
- Joseph M Schrader
- From the George and Anne Ryan Institute for Neuroscience,Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA
| | - Aleksandra Stanisavljevic
- From the George and Anne Ryan Institute for Neuroscience,Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA
| | - Feng Xu
- From the George and Anne Ryan Institute for Neuroscience,Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA
| | - William E Van Nostrand
- Send correspondence to: William E. Van Nostrand, PhD, George and Anne Ryan Institute for Neuroscience, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 130 Flagg Road, Kingston, RI 02881, USA; E-mail:
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49
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Pfister H. Neutrophil Extracellular Traps and Neutrophil-Derived Extracellular Vesicles: Common Players in Neutrophil Effector Functions. Diagnostics (Basel) 2022; 12:diagnostics12071715. [PMID: 35885618 PMCID: PMC9323717 DOI: 10.3390/diagnostics12071715] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/07/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023] Open
Abstract
Neutrophil granulocytes are a central component of the innate immune system. In recent years, they have gained considerable attention due to newly discovered biological effector functions and their involvement in various pathological conditions. They have been shown to trigger mechanisms that can either promote or inhibit the development of autoimmunity, thrombosis, and cancer. One mechanism for their modulatory effect is the release of extracellular vesicles (EVs), that trigger appropriate signaling pathways in immune cells and other target cells. In addition, activated neutrophils can release bactericidal DNA fibers decorated with proteins from neutrophil granules (neutrophil extracellular traps, NETs). While NETs are very effective in limiting pathogens, they can also cause severe damage if released in excess or cleared inefficiently. Since NETs and EVs share a variety of neutrophil molecules and initially act in the same microenvironment, differential biochemical and functional analysis is particularly challenging. This review focuses on the biochemical and functional parallels and the extent to which the overlapping spectrum of effector molecules has an impact on biological and pathological effects.
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Affiliation(s)
- Heiko Pfister
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center Munich, Technical University Munich, D-80636 Munich, Germany
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50
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Li JC, Zou XM, Yang SF, Jin JQ, Zhu L, Li CJ, Yang H, Zhang AG, Zhao TQ, Chen CY. Neutrophil extracellular traps participate in the development of cancer-associated thrombosis in patients with gastric cancer. World J Gastroenterol 2022; 28:3132-3149. [PMID: 36051331 PMCID: PMC9331535 DOI: 10.3748/wjg.v28.i26.3132] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/20/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The development of venous thromboembolism (VTE) is associated with high mortality among gastric cancer (GC) patients. Neutrophil extracellular traps (NETs) have been reported to correlate with the prothrombotic state in some diseases, but are rarely reported in GC patients.
AIM To investigate the effect of NETs on the development of cancer-associated thrombosis in GC patients.
METHODS The levels of NETs in blood and tissue samples of patients were analyzed by ELISA, flow cytometry, and immunofluorescence staining. NET generation and hypercoagulation of platelets and endothelial cells (ECs) in vitro were observed by immunofluorescence staining. NET procoagulant activity (PCA) was determined by fibrin formation and thrombin–antithrombin complex (TAT) assays. Thrombosis in vivo was measured in a murine model induced by flow stenosis in the inferior vena cava (IVC).
RESULTS NETs were likely to form in blood and tissue samples of GC patients compared with healthy individuals. In vitro studies showed that GC cells and their conditioned medium, but not gastric mucosal epithelial cells, stimulated NET release from neutrophils. In addition, NETs induced a hypercoagulable state of platelets by upregulating the expression of phosphatidylserine and P-selectin on the cells. Furthermore, NETs stimulated the adhesion of normal platelets on glass surfaces. Similarly, NETs triggered the conversion of ECs to hypercoagulable phenotypes by downregulating the expression of their intercellular tight junctions but upregulating that of tissue factor. Treatment of normal platelets or ECs with NETs augmented the level of plasma fibrin formation and the TAT complex. In the models of IVC stenosis, tumor-bearing mice showed a stronger ability to form thrombi, and NETs abundantly accumulated in the thrombi of tumor-bearing mice compared with control mice. Notably, the combination of deoxyribonuclease I, activated protein C, and sivelestat markedly abolished the PCA of NETs.
CONCLUSION GC-induced NETs strongly increased the risk of VTE development both in vitro and in vivo. NETs are potential therapeutic targets in the prevention and treatment of VTE in GC patients.
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Affiliation(s)
- Jia-Cheng Li
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xiao-Ming Zou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Shi-Feng Yang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jia-Qi Jin
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Lei Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Chang-Jian Li
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Hao Yang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - An-Ge Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Tian-Qi Zhao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Chong-Yan Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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