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Lei W, Li X, Li S, Zhou F, Guo Y, Zhang M, Jin X, Zhang H. Targeting neutrophils extracellular traps, a promising anti-thrombotic therapy for natural products from traditional Chinese herbal medicine. Biomed Pharmacother 2024; 179:117310. [PMID: 39226727 DOI: 10.1016/j.biopha.2024.117310] [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: 05/13/2024] [Revised: 08/04/2024] [Accepted: 08/13/2024] [Indexed: 09/05/2024] Open
Abstract
Thrombi are the main cause of vascular occlusion and contribute significantly to cardiovascular events and death. Neutrophils extracellular traps (NETs)-induced thrombosis plays a vital role in thrombotic complications and it takes the main responsibility for the resistance of fibrinolysis. However, the conventional anti-thrombotic therapies are inadequate to treat NETs-induced thrombotic complications but carry a high risk of bleeding. Consequently, increased attention has shifted towards exploring novel anti-thrombotic treatments targeting NETs. Interestingly, accumulating evidences prove that natural products from traditional Chinese herbal medicines have a great potential to mitigate thrombosis through inhibiting generous NETs formation and degrading excessive NETs. In this review, we elaborated the formation and degradation of NETs and highlighted its pivotal role in immunothrombosis through interactions with platelets and coagulation factors. Since available anti-thrombotic drugs targeting NETs are deficient, we further summarized the natural products and compounds from traditional Chinese herbal medicines which exert effective actions on regulating NETs formation and also have anti-thrombotic effects. Our findings underscore the diverse effects of natural products in targeting NETs, including relieving inflammation and oxidative stress of neutrophils, inhibiting neutrophils activation and DNA efflux, suppressing granule proteins release, reducing histones and promoting DNA degradation. This review aims to highlight the significance of natural medicines in anti-thrombotic therapies through targeting NETs and to lay a groundwork for developing novel anti-thrombotic agents from traditional Chinese herbal medicines.
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Affiliation(s)
- Wei Lei
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine,10 Poyanghu Road, Jinghai District, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiao Li
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine,10 Poyanghu Road, Jinghai District, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shanze Li
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine,10 Poyanghu Road, Jinghai District, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Fengjie Zhou
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine,10 Poyanghu Road, Jinghai District, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yadi Guo
- School of Management, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Mingyan Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine,10 Poyanghu Road, Jinghai District, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xinyao Jin
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine,10 Poyanghu Road, Jinghai District, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Han Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine,10 Poyanghu Road, Jinghai District, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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Geng X, Wang DW, Li H. The pivotal role of neutrophil extracellular traps in cardiovascular diseases: Mechanisms and therapeutic implications. Biomed Pharmacother 2024; 179:117289. [PMID: 39151311 DOI: 10.1016/j.biopha.2024.117289] [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: 05/30/2024] [Revised: 08/05/2024] [Accepted: 08/08/2024] [Indexed: 08/19/2024] Open
Abstract
Cardiovascular diseases (CVDs) continue to pose a significant burden on global health, prominently contributing to morbidity and mortality rates worldwide. Recent years have witnessed an increasing recognition of the intricate involvement of neutrophil extracellular traps (NETs) in the pathology of diverse cardiovascular conditions. This review provides a comprehensive analysis of the multifaceted functions of NETs in cardiovascular diseases, shedding light on the impact on atherosclerosis, myocardial infarction, heart failure, myocarditis, atrial fibrillation, aortic stenosis, and the potential therapeutic avenues targeting NETs.
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Affiliation(s)
- Xinyu Geng
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Huihui Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Yong J, Toh CH. The convergent model of coagulation. J Thromb Haemost 2024; 22:2140-2146. [PMID: 38815754 DOI: 10.1016/j.jtha.2024.05.014] [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: 01/15/2024] [Revised: 04/18/2024] [Accepted: 05/10/2024] [Indexed: 06/01/2024]
Abstract
It is increasingly apparent that the pathologic interplay between coagulation and innate immunity, ie, immunothrombosis, forms the common basis of many challenges across the boundaries of specialized medicine and cannot be fully explained by the conventional concepts of cascade and cell-based coagulation. To improve our understanding of coagulation, we propose a model of coagulation that converges with inflammation and innate immune activation as a unified response toward vascular injury. Evolutionarily integral to the convergent response are damage-associated molecular patterns, which are released as a consequence of injury. Damage-associated molecular patterns facilitate diverse interactions within and between systems, not only to complement and reinforce cell-based clot formation but also to steer the response toward clot resolution and wound healing. By extending coagulation beyond its current boundaries, the convergent model aims to deliver novel diagnostics and therapeutics for contemporary and unexpected challenges across medicine, as exposed by COVID-19 and vaccine-induced immune thrombotic thrombocytopenia.
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Affiliation(s)
- Jun Yong
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
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4
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Kortam N, Liang W, Shiple C, Huang S, Gedert R, Clair JS, Sarosh C, Foster C, Tsou PS, Varga J, Knight JS, Khanna D, Ali RA. Elevated neutrophil extracellular traps in systemic sclerosis-associated vasculopathy and suppression by a synthetic prostacyclin analog. Arthritis Res Ther 2024; 26:139. [PMID: 39054558 PMCID: PMC11270934 DOI: 10.1186/s13075-024-03379-6] [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: 05/10/2024] [Accepted: 07/16/2024] [Indexed: 07/27/2024] Open
Abstract
OBJECTIVES Neutrophils and neutrophil extracellular traps (NETs) contribute to the vascular complications of multiple diseases, but their role in systemic sclerosis (SSc) is understudied. We sought to test the hypothesis that NETs are implicated in SSc vasculopathy and that treatment with prostacyclin analogs may ameliorate SSc vasculopathy not only through vasodilation but also by inhibiting NET release. METHODS Blood from 125 patients with SSc (87 diffuse cutaneous SSc and 38 limited cutaneous SSc) was collected at a single academic medical center. Vascular complications such as digital ulcers, pulmonary artery hypertension, and scleroderma renal crisis were recorded. The association between circulating NETs and vascular complications was determined using in vitro and ex vivo assays. The impact of the synthetic prostacyclin analog epoprostenol on NET release was determined. RESULTS Neutrophil activation and NET release were elevated in patients with SSc-associated vascular complications compared to matched patients without vascular complications. Neutrophil activation and NETs positively correlated with soluble E-selectin and VCAM-1, circulating markers of vascular injury. Treatment of patients with digital ischemia with a synthetic prostacyclin analog boosted neutrophil cyclic AMP, which was associated with the blunting of NET release and reduced NETs in circulation. CONCLUSION Our study demonstrates an association between NETs and vascular complications in SSc. We also identified the potential for an additional therapeutic benefit of synthetic prostacyclin analogs, namely to reduce neutrophil hyperactivity and NET release in SSc patients.
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Affiliation(s)
- Neda Kortam
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Wenying Liang
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Claire Shiple
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Suiyuan Huang
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Rosemary Gedert
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - James St Clair
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Cyrus Sarosh
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Caroline Foster
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Pei-Suen Tsou
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - John Varga
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Dinesh Khanna
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Ramadan A Ali
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA.
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Rysenga CE, May-Zhang L, Zahavi M, Knight JS, Ali RA. Taxifolin inhibits NETosis through activation of Nrf2 and provides protective effects in models of lupus and antiphospholipid syndrome. Rheumatology (Oxford) 2024; 63:2006-2015. [PMID: 37815837 DOI: 10.1093/rheumatology/kead547] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/06/2023] [Accepted: 10/02/2023] [Indexed: 10/11/2023] Open
Abstract
OBJECTIVES Taxifolin (dihydroquercetin) is a bioactive plant flavonoid that exhibits anti-inflammatory and anti-oxidative properties. We hypothesized that taxifolin might be an effective dietary supplement to ameliorate symptoms arising from thrombo-inflammatory diseases such as lupus and APS. METHODS We used in vitro assays and a mouse model to determine mechanisms by which taxifolin inhibits neutrophil extracellular trap (NET) formation (i.e. NETosis) and venous thrombosis in lupus and APS. RESULTS At doses ranging from 0.1 to 1 µg/ml, taxifolin inhibited NETosis from control neutrophils stimulated with autoantibodies isolated from lupus and APS patients, and its suppressive effects were mitigated by blocking the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). Furthermore, taxifolin at a dose as low as 20 mg/kg/day reduced in vivo NETosis in thrombo-inflammatory mouse models of lupus and APS while also significantly attenuating autoantibody formation, inflammatory cytokine production and large-vein thrombosis. CONCLUSION Our study is the first to demonstrate the protective effects of taxifolin in the context of lupus and APS. Importantly, our study also suggests a therapeutic potential to neutralize neutrophil hyperactivity and NETosis that could have relevance to a variety of thrombo-inflammatory diseases.
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Affiliation(s)
- Christine E Rysenga
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | - Miela Zahavi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Ramadan A Ali
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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Zhu X, Wang C, Duan X, Liang B, Genbo Xu E, Huang Z. Micro- and nanoplastics: A new cardiovascular risk factor? ENVIRONMENT INTERNATIONAL 2023; 171:107662. [PMID: 36473237 DOI: 10.1016/j.envint.2022.107662] [Citation(s) in RCA: 110] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/22/2022] [Accepted: 11/25/2022] [Indexed: 06/17/2023]
Abstract
Exposure to micro- and nanoplastics (MNPs) is inevitable due to their omnipresence in the environment. A growing body of studies has advanced our understanding of the potential toxicity of MNPs but knowledge gaps still exist regarding the adverse effects of MNPs on the cardiovascular system and underlying mechanisms, particularly in humans. Here, we reviewed up-to-date data published in the past 10 years on MNP-driven cardiovascular toxicity and mechanisms. Forty-six articles concerning ADME (absorption, distribution, and aggregation behaviors) and toxicity of MNPs in the circulatory system of animals and human cells were analyzed and summarized. The results showed that MNPs affected cardiac functions and caused toxicity on (micro)vascular sites. Direct cardiac toxicity of MNPs included abnormal heart rate, cardiac function impairment, pericardial edema, and myocardial fibrosis. On (micro)vascular sites, MNPs induced hemolysis, thrombosis, blood coagulation, and vascular endothelial damage. The main mechanisms included oxidative stress, inflammation, apoptosis, pyroptosis, and interaction between MNPs and multiple cellular components. Cardiovascular toxicity was determined by the properties (type, size, surface, and structure) of MNPs, exposure dose and duration, protein presence, the life stage, sex, and species of the tested organisms, as well as the interaction with other environmental contamination. The limited quantitative information on MNPs' ADME and the lack of guidelines for MNP cardiotoxicity testing makes risk assessment on cardiac health impossible. Furthermore, the future directions of cardiovascular research on MNPs are recommended to enable more realistic health risk assessment.
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Affiliation(s)
- Xiaoqi Zhu
- NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Chuanxuan Wang
- NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Xiaoyu Duan
- Department of Biology, University of Southern Denmark, Odense 5230, Denmark
| | - Boxuan Liang
- NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Elvis Genbo Xu
- Department of Biology, University of Southern Denmark, Odense 5230, Denmark.
| | - Zhenlie Huang
- NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou 510515, China.
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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: 31] [Impact Index Per Article: 15.5] [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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Zhang Z, Huang W, Ren F, Luo L, Zhou J, Tian M, Wang Z, Chen D, Tang L. Analysis of Risk Factors and the Establishment of a Predictive Model for Thrombosis in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Int J Gen Med 2022; 15:8071-8079. [DOI: 10.2147/ijgm.s384624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/10/2022] [Indexed: 11/09/2022] Open
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Citrullination: A modification important in the pathogenesis of autoimmune diseases. Clin Immunol 2022; 245:109134. [DOI: 10.1016/j.clim.2022.109134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/13/2022] [Accepted: 09/19/2022] [Indexed: 11/18/2022]
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Peng Y, Wu X, Zhang S, Deng C, Zhao L, Wang M, Wu Q, Yang H, Zhou J, Peng L, Luo X, Chen Y, Wang A, Xiao Q, Zhang W, Zhao Y, Zeng X, Fei Y. The potential roles of type I interferon activated neutrophils and neutrophil extracellular traps (NETs) in the pathogenesis of primary Sjögren's syndrome. Arthritis Res Ther 2022; 24:170. [PMID: 35854322 PMCID: PMC9295258 DOI: 10.1186/s13075-022-02860-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 07/07/2022] [Indexed: 11/22/2022] Open
Abstract
Objective Neutrophils and aberrant NETosis have been implicated in the pathogenesis of diverse autoimmune diseases; however, their roles in primary Sjögren’s syndrome (pSS) remain unclear. We aimed to reveal the potential roles of neutrophils and neutrophil extracellular traps (NETs) in pSS. Methods pSS patients were enrolled and NETosis markers were measured in plasma and labial glands using ELISA and immunofluorescence. The gene signatures of neutrophils were assessed by RNA-Seq and RT-PCR. Reactive oxygen species (ROS), mitochondrial ROS (MitoSOX) production, and JC-1 were measured by flow cytometry. Results NETosis markers including cell-free DNA (cf-DNA) and myeloperoxidase (MPO) in plasma and labial glands from pSS patients were significantly higher than healthy controls (HCs) and were associated with disease activity. RNA sequencing and RT-qPCR revealed activated type I IFN signaling pathway and higher expression of genes related to type I interferon in pSS neutrophils. Further stimulating with IFN-α 2a in vitro significantly induced ROS production and JC-1 monomer percentage in pSS neutrophils. Conclusions Our data suggest the involvement of neutrophils and enhanced NETosis in pSS patients. Further mechanism study in vitro revealed that type I IFN activation in pSS neutrophils led to mitochondrial damage and related ROS production which finally result in the generation of NETs. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02860-4.
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Affiliation(s)
- Yu Peng
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Xunyao Wu
- Clinical Biobank, Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shulan Zhang
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Chuiwen Deng
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Lidan Zhao
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Mu Wang
- Department of Stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Qingjun Wu
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Huaxia Yang
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Jiaxin Zhou
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Linyi Peng
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Xuan Luo
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Yingying Chen
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Anqi Wang
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Qiufeng Xiao
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Wen Zhang
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Yan Zhao
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Xiaofeng Zeng
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China
| | - Yunyun Fei
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, 100730, China.
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11
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de Freitas Junior RA, Lossavaro PKDMB, Kassuya CAL, Paredes-Gamero EJ, Farias Júnior NC, Souza MIL, Silva-Comar FMDS, Cuman RKN, Silva DB, Toffoli-Kadri MC, Silva-Filho SE. Effect of Ylang-Ylang ( Cananga odorata Hook. F. & Thomson) Essential Oil on Acute Inflammatory Response In Vitro and In Vivo. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123666. [PMID: 35744789 PMCID: PMC9231162 DOI: 10.3390/molecules27123666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/05/2022] [Accepted: 05/16/2022] [Indexed: 11/16/2022]
Abstract
The aim of this study is to evaluate the phytochemical profile, oral acute toxicity, and the effect of ylang-ylang (Cananga odorata Hook. F. & Thomson) essential oil (YEO) on acute inflammation. YEO was analyzed by gas chromatography/mass spectrometry. For in vitro tests, YEO was assessed using cytotoxicity, neutrophil chemotaxis induced by N-formyl methionyl leucyl phenylalanine (fMLP), and phagocytic activity tests. YEO was orally administered in zymosan-induced peritonitis, carrageenan-induced leukocyte rolling, and adhesion events in the in situ microcirculation model and in carrageenan-induced paw edema models. YEO (2000 mg/kg) was also tested using an acute toxicity test in Swiss mice. YEO showed a predominance of benzyl acetate, linalool, benzyl benzoate, and methyl benzoate. YEO did not present in vitro cytotoxicity. YEO reduced the in vitro neutrophil chemotaxis induced by fMLP and reduced the phagocytic activity. The oral treatment with YEO reduced the leukocyte recruitment and nitric oxide production in the zymosan-induced peritonitis model, reduced rolling and adherent leukocyte number induced by carrageenan in the in situ microcirculation model, and reduced carrageenan-induced edema and mechanical hyperalgesia. YEO did not present signs of toxicity in the acute toxicity test. In conclusion, YEO affected the leukocyte activation, and presented antiedematogenic, anti-hyperalgesic, and anti-inflammatory properties.
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Affiliation(s)
- Robson Araújo de Freitas Junior
- Pharmaceutical Sciences, Food and Nutrition College, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, Brazil; (R.A.d.F.J.); (P.K.d.M.B.L.); (E.J.P.-G.); (D.B.S.); (M.C.T.-K.)
| | - Paloma Kênia de Moraes Berenguel Lossavaro
- Pharmaceutical Sciences, Food and Nutrition College, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, Brazil; (R.A.d.F.J.); (P.K.d.M.B.L.); (E.J.P.-G.); (D.B.S.); (M.C.T.-K.)
| | | | - Edgar Julian Paredes-Gamero
- Pharmaceutical Sciences, Food and Nutrition College, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, Brazil; (R.A.d.F.J.); (P.K.d.M.B.L.); (E.J.P.-G.); (D.B.S.); (M.C.T.-K.)
| | | | - Maria Inês Lenz Souza
- Biosciences Institute, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, Brazil;
| | | | - Roberto Kenji Nakamura Cuman
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá 87020-900, Brazil; (F.M.d.S.S.-C.); (R.K.N.C.)
| | - Denise Brentan Silva
- Pharmaceutical Sciences, Food and Nutrition College, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, Brazil; (R.A.d.F.J.); (P.K.d.M.B.L.); (E.J.P.-G.); (D.B.S.); (M.C.T.-K.)
| | - Mônica Cristina Toffoli-Kadri
- Pharmaceutical Sciences, Food and Nutrition College, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, Brazil; (R.A.d.F.J.); (P.K.d.M.B.L.); (E.J.P.-G.); (D.B.S.); (M.C.T.-K.)
| | - Saulo Euclides Silva-Filho
- Pharmaceutical Sciences, Food and Nutrition College, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, Brazil; (R.A.d.F.J.); (P.K.d.M.B.L.); (E.J.P.-G.); (D.B.S.); (M.C.T.-K.)
- Correspondence:
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12
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Markers of NET formation and stroke risk in patients with atrial fibrillation: association with a prothrombotic state. Thromb Res 2022; 213:1-7. [DOI: 10.1016/j.thromres.2022.02.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/14/2022] [Accepted: 02/28/2022] [Indexed: 01/05/2023]
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13
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Zhou Y, Tao W, Shen F, Du W, Xu Z, Liu Z. The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis. Front Cardiovasc Med 2021; 8:786387. [PMID: 34926629 PMCID: PMC8674622 DOI: 10.3389/fcvm.2021.786387] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 10/29/2021] [Indexed: 12/16/2022] Open
Abstract
Neutrophils play a vital role in the formation of arterial, venous and cancer-related thrombosis. Recent studies have shown that in a process known as NETosis, neutrophils release proteins and enzymes complexed to DNA fibers, collectively called neutrophil extracellular traps (NETs). Although NETs were originally described as a way for the host to capture and kill bacteria, current knowledge indicates that NETs also play an important role in thrombosis. According to recent studies, the destruction of vascular microenvironmental homeostasis and excessive NET formation lead to pathological thrombosis. In vitro experiments have found that NETs provide skeletal support for platelets, red blood cells and procoagulant molecules to promote thrombosis. The protein components contained in NETs activate the endogenous coagulation pathway to promote thrombosis. Therefore, NETs play an important role in the formation of arterial thrombosis, venous thrombosis and cancer-related thrombosis. This review will systematically summarize and explain the study of NETs in thrombosis in animal models and in vivo experiments to provide new targets for thrombosis prevention and treatment.
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Affiliation(s)
- Yilu Zhou
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Weimin Tao
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fuyi Shen
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Weijia Du
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhendong Xu
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhiqiang Liu
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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14
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Sun M, Ding R, Ma Y, Sun Q, Ren X, Sun Z, Duan J. Cardiovascular toxicity assessment of polyethylene nanoplastics on developing zebrafish embryos. CHEMOSPHERE 2021; 282:131124. [PMID: 34374342 DOI: 10.1016/j.chemosphere.2021.131124] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/14/2021] [Accepted: 06/03/2021] [Indexed: 06/13/2023]
Abstract
Environmental exposure to nanoplastics is inevitable as the application of nanoplastics in our daily life is more and more extensively. So, the adverse effects of nanoplastics on human health are also gaining greater concerns. However, the subsequent toxicological response to nanoplastics, especially on cardiovascular damage was still largely unknown. In this regard, the evaluation of cardiovascular effects of nanoplastics was performed in zebrafish embryos. The results indicated that the no observed adverse effect level (NOAEL) of nanoplastics is 50 μg/mL. The pericardial toxicity and hemodynamic changes were assessed by Albino (melanin allele) mutant zebrafish line. Severe pericardial edema was observed in zebrafish embryos after exposure to nanoplastics. At the concentration higher than NOAEL, nanoplastics significantly decreased the cardiac output (CO) and blood flow velocity. The fluorescence images manifested that the nanoplastics could inhibit the subintestinal angiogenesis of transgenic zebrafish embryos line Tg (fli-1: EGFP), which might disturb the cardiovascular formation and development. The resulting vascular endothelial dysfunction and hypercoagulable state of circulating blood further accelerated thrombosis. Reactive oxidative stress (ROS) and systemic inflammation were also found in Wild AB and Tg (mpo: GFP) zebrafish embryos, respectively. We also found many neutrophils recruiting in the tail vein where the zebrafish embryo thrombosis occurred. Our data suggested that nanoplastics could trigger the cardiovascular toxicity in zebrafish embryos, which could provide an essential clue for the safety assessment of nanoplastics.
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Affiliation(s)
- Mengqi Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Ruiyang Ding
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Yiming Ma
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Qinglin Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Xiaoke Ren
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China.
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15
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Liapi M, Jayne D, Merkel PA, Segelmark M, Mohammad AJ. Venous thromboembolism in ANCA-associated vasculitis: a population-based cohort study. Rheumatology (Oxford) 2021; 60:4616-4623. [PMID: 33506869 DOI: 10.1093/rheumatology/keab057] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 01/04/2021] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To determine incidence rate and predictors of venous thromboembolic events (VTE) in a population-based cohort with ANCA-associated vasculitis (AAV). METHODS The study comprised 325 patients diagnosed with AAV from 1997 to 2016. All cases of VTE from prior to vasculitis diagnosis to the end of the study period were identified. The BVAS was used to assess disease activity at diagnosis. Venous thromboembolisms occurring in a period beginning 3 months prior to AAV diagnosis were considered to be AAV-related. The standardized incidence ratio (SIR) and 95% CI of VTE were calculated using the incidence rate in the general population. RESULTS Fifty-nine patients (18%) suffered 64 VTE events. Of these, 48 (81%) suffered AAV-related VTE [deep vein thrombosis (n = 23), pulmonary embolism (n = 18) and other (n = 9)]. The incidence rate of AAV-related VTE was 2.4 per 100 person-years (95% CI 1.7, 3.0) during 2039 person-years of follow-up. The incidence during the first 3 months post-AAV diagnosis was 20.4 per 100 person-years (95% CI 11.5, 29.4), decreasing to 8.9 (95% CI 0.2, 17.6) and 1.5 (95% CI 0.0, 3.5) in months 4-6 and months 7-12 post-AAV diagnosis, respectively. The SIR was 34.2 (95% CI 20.2, 48.1) for deep vein thrombosis and 10.4 (95% CI 5.6, 15.1) for pulmonary embolism. In multivariate Cox regression analyses, only age and BVAS were predictive of VTE. CONCLUSIONS The incidence rate and SIR of AAV-related VTE is high, and higher early in the course of the disease. Vasculitis activity and age are positively associated with VTE.
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Affiliation(s)
- Matina Liapi
- Department of Clinical Sciences Lund, Section of Rheumatology, Skåne University Hospital, Lund University, Lund, Sweden
| | - David Jayne
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Peter A Merkel
- Division of Rheumatology, Department of Medicine.,Division of Epidemiology, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA
| | - Mårten Segelmark
- Department of Clinical Sciences Lund, Lund University, Nephrology, Lund, Sweden
| | - Aladdin J Mohammad
- Department of Clinical Sciences Lund, Section of Rheumatology, Skåne University Hospital, Lund University, Lund, Sweden.,Department of Medicine, University of Cambridge, Cambridge, UK
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16
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Vianello A, Guarnieri G, Braccioni F, Molena B, Lococo S, Achille A, Lionello F, Salviati L, Caminati M, Senna G. Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses. J Clin Med 2021; 10:4493. [PMID: 34640510 PMCID: PMC8509830 DOI: 10.3390/jcm10194493] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 12/24/2022] Open
Abstract
The most common hereditary disorder in adults, α1-antitrypsin deficiency (AATD), is characterized by reduced plasma levels or the abnormal functioning of α1-antitrypsin (AAT), a major human blood serine protease inhibitor, which is encoded by the SERine Protein INhibitor-A1 (SERPINA1) gene and produced in the liver. Recently, it has been hypothesized that the geographic differences in COVID-19 infection and fatality rates may be partially explained by ethnic differences in SERPINA1 allele frequencies. In our review, we examined epidemiological data on the correlation between the distribution of AATD, SARS-CoV-2 infection, and COVID-19 mortality rates. Moreover, we described shared pathogenetic pathways that may provide a theoretical basis for our epidemiological findings. We also considered the potential use of AAT augmentation therapy in patients with COVID-19.
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Affiliation(s)
- Andrea Vianello
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, 35122 Padova, Italy; (G.G.); (F.B.); (B.M.); (S.L.); (A.A.); (F.L.)
| | - Gabriella Guarnieri
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, 35122 Padova, Italy; (G.G.); (F.B.); (B.M.); (S.L.); (A.A.); (F.L.)
| | - Fausto Braccioni
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, 35122 Padova, Italy; (G.G.); (F.B.); (B.M.); (S.L.); (A.A.); (F.L.)
| | - Beatrice Molena
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, 35122 Padova, Italy; (G.G.); (F.B.); (B.M.); (S.L.); (A.A.); (F.L.)
| | - Sara Lococo
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, 35122 Padova, Italy; (G.G.); (F.B.); (B.M.); (S.L.); (A.A.); (F.L.)
| | - Alessia Achille
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, 35122 Padova, Italy; (G.G.); (F.B.); (B.M.); (S.L.); (A.A.); (F.L.)
| | - Federico Lionello
- Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padova, 35122 Padova, Italy; (G.G.); (F.B.); (B.M.); (S.L.); (A.A.); (F.L.)
| | - Leonardo Salviati
- Department of Pediatrics, University of Padova, 35122 Padova, Italy;
| | - Marco Caminati
- Asthma Center and Allergy Unit, University of Verona, 37129 Verona, Italy; (M.C.); (G.S.)
| | - Gianenrico Senna
- Asthma Center and Allergy Unit, University of Verona, 37129 Verona, Italy; (M.C.); (G.S.)
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17
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Natorska J, Kopytek M, Undas A. Aortic valvular stenosis: Novel therapeutic strategies. Eur J Clin Invest 2021; 51:e13527. [PMID: 33621361 DOI: 10.1111/eci.13527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/19/2021] [Accepted: 02/22/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Aortic stenosis (AS) prevalence is estimated to reach 4.5 million cases worldwide by the year 2030. AS is a progressive disease without a pharmacological treatment. In the current review, we aimed to investigate novel therapeutic approaches for non-surgical AS treatment, at least in patients with mild-to-moderate AS. MATERIALS AND METHODS The most recent and relevant papers concerned with novel molecular pathways that have potential as therapeutic targets in AS were selected from searches of PubMed and Web of Science up to February 2021. RESULTS Growing evidence indicates that therapies using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, simvastatin/ezetimibe combination, cholesteryl ester transfer protein inhibitors or antisense oligonucleotides targeting apolipoprotein(a) reduce the risk of AS progression. It has been shown that enhanced valvular lipid oxidation may drive AS development by leading to the activation of valvular interstitial cells (VICs), the most abundant valvular cells having a major contribution to valve calcification. Since VICs are able to release pro-inflammatory cytokines, clotting factors and proteins involved in calcification, strategies targeting these cell activations seem promising as therapeutic interventions. Recently, non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to inhibit activation of VICs. CONCLUSION Several novel molecular pathways of AS development have been identified over the past few years. Therapies using PCSK9 inhibitors, simvastatin/ezetimibe combination, lipoprotein(a)-lowering therapy are highly promising candidates as therapeutics in the prevention of mild AS progression, while preclinical studies show that NOACs may inhibit valvular inflammation and coagulation activation and slower the rate of AS progression.
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Affiliation(s)
- Joanna Natorska
- John Paul II Hospital, Kraków, Poland.,Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
| | - Magdalena Kopytek
- John Paul II Hospital, Kraków, Poland.,Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
| | - Anetta Undas
- John Paul II Hospital, Kraków, Poland.,Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
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18
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Mauracher LM, Krall M, Roiß J, Hell L, Koder S, Hofbauer TM, Gebhart J, Hayden H, Brostjan C, Ay C, Pabinger I. Neutrophil subpopulations and their activation potential in patients with antiphospholipid syndrome and healthy individuals. Rheumatology (Oxford) 2021; 60:1687-1699. [PMID: 33026085 PMCID: PMC8024003 DOI: 10.1093/rheumatology/keaa532] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/27/2020] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Patients with APS are at increased risk of thromboembolism. Neutrophils have been shown to play a role in inducing thrombosis. We aimed to investigate differences in neutrophil subpopulations, their potential of activation and neutrophil extracellular trap (NET) formation comparing high and low-density neutrophils (HDNs/LDNs) as well as subpopulations in patients with APS and controls to gain deeper insight into their potential role in thrombotic manifestations in patients with APS. METHODS HDNs and LDNs of 20 patients with APS and 20 healthy donors were isolated by density gradient centrifugation and stimulated. Neutrophil subpopulations, their activation and NET release were assessed by flow cytometry. RESULTS LDNs of both groups showed higher baseline activation, lower response to stimulation (regulation of activation markers CD11b/CD66b), but higher NET formation compared with HDNs. In patients with APS, the absolute number of LDNs was higher compared with controls. HDNs of APS patients showed higher spontaneous activation [%CD11b high: median (interquartile range): 2.78% (0.58-10.24) vs 0.56% (0.19-1.37)] and response to stimulation with ionomycin compared with HDNs of healthy donors [%CD11b high: 98.20 (61.08-99.13) vs 35.50% (13.50-93.85)], whereas no difference was found in LDNs. NET formation was increased in patients' HDNs upon stimulation. CONCLUSION HDNs and LDNs act differently, unstimulated and upon various stimulations in both healthy controls and APS patients. Differences in HDNs and LDNs between patients with APS and healthy controls indicate that neutrophils may enhance the risk of thrombosis in these patients and could thus be a target for prevention of thrombosis in APS.
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Affiliation(s)
- Lisa-Marie Mauracher
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Vienna, Austria
| | - Moritz Krall
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Vienna, Austria
| | - Johanna Roiß
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Vienna, Austria
| | - Lena Hell
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Vienna, Austria
| | - Silvia Koder
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Vienna, Austria
| | - Thomas M Hofbauer
- Division of Cardiology, Department of Internal Medicine II, Vienna, Austria
| | - Johanna Gebhart
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Vienna, Austria
| | - Hubert Hayden
- Department of Surgery, Surgical Research Laboratories, Medical University of Vienna, Vienna, Austria
| | - Christine Brostjan
- Department of Surgery, Surgical Research Laboratories, Medical University of Vienna, Vienna, Austria
| | - Cihan Ay
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Vienna, Austria
| | - Ingrid Pabinger
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Vienna, Austria
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19
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Águila S, de los Reyes-García AM, Fernández-Pérez MP, Reguilón-Gallego L, Zapata-Martínez L, Ruiz-Lorente I, Vicente V, González-Conejero R, Martínez C. MicroRNAs as New Regulators of Neutrophil Extracellular Trap Formation. Int J Mol Sci 2021; 22:ijms22042116. [PMID: 33672737 PMCID: PMC7924615 DOI: 10.3390/ijms22042116] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/15/2021] [Accepted: 02/18/2021] [Indexed: 12/27/2022] Open
Abstract
Neutrophil extracellular traps (NETs) are formed after neutrophils expelled their chromatin content in order to primarily capture and eliminate pathogens. However, given their characteristics due in part to DNA and different granular proteins, NETs may induce a procoagulant response linking inflammation and thrombosis. Unraveling NET formation molecular mechanisms as well as the intracellular elements that regulate them is relevant not only for basic knowledge but also to design diagnostic and therapeutic tools that may prevent their deleterious effects observed in several inflammatory pathologies (e.g., cardiovascular and autoimmune diseases, cancer). Among the potential elements involved in NET formation, several studies have investigated the role of microRNAs (miRNAs) as important regulators of this process. miRNAs are small non-coding RNAs that have been involved in the control of almost all physiological processes in animals and plants and that are associated with the development of several pathologies. In this review, we give an overview of the actual knowledge on NETs and their implication in pathology with a special focus in cardiovascular diseases. We also give a brief overview on miRNA biology to later focus on the different miRNAs implicated in NET formation and the perspectives opened by the presented data.
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Affiliation(s)
| | | | | | | | | | | | | | - Rocío González-Conejero
- Correspondence: (R.G.-C.); (C.M.); Tel.: +34-968341990 (R.G.-C. & C.M.); Fax: +34-968261914 (R.G.-C. & C.M.)
| | - Constantino Martínez
- Correspondence: (R.G.-C.); (C.M.); Tel.: +34-968341990 (R.G.-C. & C.M.); Fax: +34-968261914 (R.G.-C. & C.M.)
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20
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Ali RA, Gandhi AA, Dai L, Weiner J, Estes SK, Yalavarthi S, Gockman K, Sun D, Knight JS. Antineutrophil properties of natural gingerols in models of lupus. JCI Insight 2021; 6:138385. [PMID: 33373329 PMCID: PMC7934838 DOI: 10.1172/jci.insight.138385] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 12/16/2020] [Indexed: 12/23/2022] Open
Abstract
Ginger is known to have antiinflammatory and antioxidative effects and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report antineutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that is at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints, such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to our knowledge to demonstrate a protective role for ginger-derived compounds in the context of lupus. Importantly, it provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.
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Affiliation(s)
- Ramadan A Ali
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Alex A Gandhi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Lipeng Dai
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Julia Weiner
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Shanea K Estes
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Srilakshmi Yalavarthi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Kelsey Gockman
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Emerging Role of Neutrophils in the Thrombosis of Chronic Myeloproliferative Neoplasms. Int J Mol Sci 2021; 22:ijms22031143. [PMID: 33498945 PMCID: PMC7866001 DOI: 10.3390/ijms22031143] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/10/2021] [Accepted: 01/20/2021] [Indexed: 12/11/2022] Open
Abstract
Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.
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22
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Bai X, Hippensteel J, Leavitt A, Maloney JP, Beckham D, Garcia C, Li Q, Freed BM, Ordway D, Sandhaus RA, Chan ED. Hypothesis: Alpha-1-antitrypsin is a promising treatment option for COVID-19. Med Hypotheses 2021; 146:110394. [PMID: 33239231 PMCID: PMC7659642 DOI: 10.1016/j.mehy.2020.110394] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/12/2020] [Accepted: 11/06/2020] [Indexed: 01/08/2023]
Abstract
No definitive treatment for COVID-19 exists although promising results have been reported with remdesivir and glucocorticoids. Short of a truly effective preventive or curative vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate COVID-19. We posit at least seven different mechanisms by which AAT may alleviate COVID-19. First, AAT is a serine protease inhibitor (SERPIN) shown to inhibit TMPRSS-2, the host serine protease that cleaves the spike protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of COVID-19. Fourth, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially injurious neutrophils and implicated in acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of bradykinin, reducing the ability of bradykinin to cause a capillary leak in COVID-19. Fifth, AAT inhibits thrombin, and venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in COVID-19. Sixth, AAT inhibition of elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived DNA, histones, and proteases, and implicated in the immunothrombosis of COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated acute lung injury, multi-organ dysfunction, and pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-phospholipid antibodies are increased in both COVID-19 and non-COVID pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat COVID-19 and should be studied.
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Affiliation(s)
- Xiyuan Bai
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA; Departments of Academic Affairs and Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary Sciences and Critical Care Medicine, USA
| | - Joseph Hippensteel
- Division of Pulmonary Sciences and Critical Care Medicine, USA; Denver Health, Denver, CO, USA
| | | | - James P Maloney
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA; Division of Pulmonary Sciences and Critical Care Medicine, USA
| | - David Beckham
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA; Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Cindy Garcia
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Qing Li
- Departments of Academic Affairs and Medicine, National Jewish Health, Denver, CO, USA; School of Public Health, San Diego State University, San Diego, CA, USA
| | - Brian M Freed
- Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Diane Ordway
- Department of Microbiology, Immunlogy, and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Robert A Sandhaus
- Departments of Academic Affairs and Medicine, National Jewish Health, Denver, CO, USA
| | - Edward D Chan
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA; Departments of Academic Affairs and Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary Sciences and Critical Care Medicine, USA.
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23
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Antovic A, Svensson E, Lövström B, Illescas VB, Nordin A, Börjesson O, Arnaud L, Bruchfeld A, Gunnarsson I. Venous thromboembolism in anti-neutrophil cytoplasmic antibody-associated vasculitis: an underlying prothrombotic condition? Rheumatol Adv Pract 2020; 4:rkaa056. [PMID: 33215056 PMCID: PMC7661844 DOI: 10.1093/rap/rkaa056] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/11/2020] [Indexed: 12/20/2022] Open
Abstract
Objectives We investigated the incidence and potential underlying risk factors of venous thromboembolism (VTE) in patients with AAV. We assessed haemostatic disturbances and factors that might contribute to the risk of development of VTE. Methods ANCA-positive AAV patients (n = 187) were included. Previously identified risk factors for VTE and current medication were retrieved from the medical records. We assessed haemostasis using different methods [endogenous thrombin potential (ETP), overall haemostatic potential (OHP), overall coagulation potential (OCP) and overall fibrinolysis potential (OFP)] in patients with active AAV (n = 19), inactive AAV (n = 15) and healthy controls (n = 15). Results Twenty-eight VTEs occurred in 24 patients over a total follow-up time of 1020 person-years. A majority of VTEs occurred within the first year after diagnosis. Old age (P < 0.01), ongoing prednisolone treatment and recent rituximab administration were more common in the VTE group (P < 0.05 for all). ETP and OHP were significantly increased and OFP significantly decreased in plasma from active compared with inactive AAV patients (P < 0.05, P < 0.01 and P < 0.05, respectively) and healthy controls (P < 0.001). We could not confirm previously reported risk factors for VTE development. Conclusion A high prevalence of VTE in AAV patients was seen within the first year after diagnosis, suggesting that disease activity contributes to development of VTE. Old age and concurrent treatment should also be taken into account when estimating VTE risk. The results also indicate disturbances in the haemostatic balance towards pro-thrombotic conditions in AAV patients, where ETP and OHP might be useful markers for identifying patients at high risk.
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Affiliation(s)
- Aleksandra Antovic
- Department of Medicine, Division of Rheumatology, Karolinska Institutet.,Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Einar Svensson
- Department of Medicine, Division of Rheumatology, Karolinska Institutet
| | - Björn Lövström
- Department of Medicine, Division of Rheumatology, Karolinska Institutet.,Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | | | - Annica Nordin
- Department of Medicine, Division of Rheumatology, Karolinska Institutet
| | - Ola Börjesson
- Department of Medicine, Division of Rheumatology, Karolinska Institutet.,Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Laurent Arnaud
- Department of Rheumatology, Hôpitaux Universitaires de Strasbourg, Centre National de Références des Maladies Systémiques et Autoimmunes Rares Est Sud-Ouest (RESO), Université de Strasbourg, Strasbourg, France
| | - Annette Bruchfeld
- Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, Sweden
| | - Iva Gunnarsson
- Department of Medicine, Division of Rheumatology, Karolinska Institutet.,Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
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Safari H, Kelley WJ, Saito E, Kaczorowski N, Carethers L, Shea LD, Eniola-Adefeso O. Neutrophils preferentially phagocytose elongated particles-An opportunity for selective targeting in acute inflammatory diseases. SCIENCE ADVANCES 2020; 6:eaba1474. [PMID: 32577517 PMCID: PMC7286665 DOI: 10.1126/sciadv.aba1474] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 04/14/2020] [Indexed: 05/18/2023]
Abstract
Polymeric particles have recently been used to modulate the behavior of immune cells in the treatment of various inflammatory conditions. However, there is little understanding of how physical particle parameters affect their specific interaction with different leukocyte subtypes. While particle shape is known to be a crucial factor in their phagocytosis by macrophages, where elongated particles are reported to experience reduced uptake, it remains unclear how shape influences phagocytosis by circulating phagocytes, including neutrophils that are the most abundant leukocyte in human blood. In this study, we investigated the phagocytosis of rod-shaped polymeric particles by human neutrophils relative to other leukocytes. In contrast to macrophages and other mononuclear phagocytes, neutrophils were found to exhibit increased internalization of rods in ex vivo and in vivo experimentation. This result suggests that alteration of particle shape can be used to selectively target neutrophils in inflammatory pathologies where these cells play a substantial role.
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Affiliation(s)
- Hanieh Safari
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - William J. Kelley
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eiji Saito
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nicholas Kaczorowski
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lauren Carethers
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lonnie D. Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Omolola Eniola-Adefeso
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
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25
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Lu Y, Dong Y, Zhang Y, Shen D, Wang X, Ge R, Zhang M, Xia Y, Wang X. Antiphospholipid antibody-activated NETs exacerbate trophoblast and endothelial cell injury in obstetric antiphospholipid syndrome. J Cell Mol Med 2020; 24:6690-6703. [PMID: 32369873 PMCID: PMC7299718 DOI: 10.1111/jcmm.15321] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 03/07/2020] [Accepted: 04/09/2020] [Indexed: 12/13/2022] Open
Abstract
Despite the widespread use of antiplatelets and anticoagulants, women with antiphospholipid syndrome (APS) may face pregnancy complications associated with placental dysplasia. Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many autoimmune diseases, including vascular APS; however, their role in obstetric APS is unclear. Herein, we investigated the role of NETs by quantifying cell‐free DNA and NET marker levels. Live‐cell imaging was used to visualize NET formation, and MAPK signalling pathway proteins were analysed. Cell migration, invasion and tube formation assays were performed to observe the effects of NETs on trophoblasts and human umbilical vein endothelial cells (HUVECs). The concentrations of cell‐free DNA and NETs in sera of pregnant patients with APS were elevated compared with that of healthy controls (HCs) matched to gestational week. APS neutrophils were predisposed to spontaneous NET release and IgG purified from the patients (APS‐IgG) induced neutrophils from HCs to release NETs. Additionally, APS‐IgG NET induction was abolished with inhibitors of reactive oxygen species, AKT, p38 MAPK and ERK1/2. Moreover, NETs were detrimental to trophoblasts and HUVECs. In summary, APS‐IgG‐induced NET formation deserves further investigation as a potential novel therapeutic target in obstetrical APS.
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Affiliation(s)
- Yuan Lu
- Department of Obstetrics and Gynaecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Yan Dong
- Department of Obstetrics and Gynaecology, Linyi People's Hospital, Linyi, China
| | - Yan Zhang
- Department of Obstetrics and Gynaecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Di Shen
- Department of Obstetrics and Gynaecology, Maternal and Child Health Care of Shandong Province, Jinan, China
| | - Xiyao Wang
- Department of Obstetrics and Gynaecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Ruxiu Ge
- Department of Obstetrics and Gynaecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Meihua Zhang
- The Laboratory of Placenta-Related Diseases, Key Laboratory of Birth Regulation and Control Technology of National Health and Family Planning Commission of China, Jinan, China
| | - Yu Xia
- Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xietong Wang
- Department of Obstetrics and Gynaecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Department of Obstetrics and Gynaecology, Maternal and Child Health Care of Shandong Province, Jinan, China.,The Laboratory of Placenta-Related Diseases, Key Laboratory of Birth Regulation and Control Technology of National Health and Family Planning Commission of China, Jinan, China
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26
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Sule G, Kelley WJ, Gockman K, Yalavarthi S, Vreede AP, Banka AL, Bockenstedt PL, Eniola-Adefeso O, Knight JS. Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by β2 Integrin Mac-1. Arthritis Rheumatol 2020; 72:114-124. [PMID: 31353826 PMCID: PMC6935403 DOI: 10.1002/art.41057] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 07/23/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVE While the role of antiphospholipid antibodies in activating endothelial cells has been extensively studied, the impact of these antibodies on the adhesive potential of leukocytes has received less attention. This study was undertaken to investigate the extent to which antiphospholipid syndrome (APS) neutrophils adhere to resting endothelial cells under physiologic flow conditions and the surface molecules required for that adhesion. METHODS Patients with primary APS (n = 43), patients with a history of venous thrombosis but negative test results for antiphospholipid antibodies (n = 11), and healthy controls (n = 38) were studied. Cells were introduced into a flow chamber and perfused across resting human umbilical vein endothelial cells (HUVECs). Surface adhesion molecules were quantified by flow cytometry. Neutrophil extracellular trap release (NETosis) was assessed in neutrophil-HUVEC cocultures. RESULTS Upon perfusion of anticoagulated blood through the flow chamber, APS neutrophils demonstrated increased adhesion as compared to control neutrophils under conditions representative of either venous (n = 8; P < 0.05) or arterial (n = 15; P < 0.0001) flow. At the same time, APS neutrophils were characterized by up-regulation of CD64, CEACAM1, β2 -glycoprotein I, and activated Mac-1 on their surface (n = 12-18; P < 0.05 for all markers). Exposing control neutrophils to APS plasma or APS IgG resulted in increased neutrophil adhesion (n = 10-11; P < 0.0001) and surface marker up-regulation as compared to controls. A monoclonal antibody specific for activated Mac-1 reduced the adhesion of APS neutrophils in the flow-chamber assay (P < 0.01). The same monoclonal antibody reduced NETosis in neutrophil-HUVEC cocultures (P < 0.01). CONCLUSION APS neutrophils demonstrate increased adhesive potential, which is dependent upon the activated form of Mac-1. In patients, this could lower the threshold for neutrophil-endothelium interactions, NETosis, and possibly thrombotic events.
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Affiliation(s)
- Gautam Sule
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - William J. Kelley
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Kelsey Gockman
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Srilakshmi Yalavarthi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Andrew P. Vreede
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Alison L. Banka
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Paula L. Bockenstedt
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | | | - Jason S. Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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27
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Flessa CM, Vlachiotis S, Nezos A, Andreakos E, Mavragani CP, Tektonidou MG. Independent association of low IFNλ1 gene expression and type I IFN score/IFNλ1 ratio with obstetric manifestations and triple antiphospholipid antibody positivity in primary antiphospholipid syndrome. Clin Immunol 2019; 209:108265. [PMID: 31639447 DOI: 10.1016/j.clim.2019.108265] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/24/2019] [Accepted: 09/30/2019] [Indexed: 12/28/2022]
Abstract
Recent data suggest an important role of type I interferons (IFN) in antiphospholipid syndrome (APS). Here we aimed to evaluate the interplay of type I and type III (or IFNλs) IFNs in APS and potential clinical and serological associations. Our findings suggest that patients with primary APS (PAPS) and systemic lupus erythematosus (SLE)/APS displayed increased type I IFN scores but decreased IFNλ1 gene expression levels compared to healthy individuals, as assessed with real-time qPCR analysis in isolated peripheral blood mononuclear cells (PBMCs). Type I IFN score/IFNλ1 ratio was remarkably higher in patients with PAPS and SLE/APS as well as in SLE patients with or without antiphospholipid antibodies (aPL) vs controls. In conclusion, our results reveal an association between low IFNλ1 expression and obstetric APS. Moreover, the type I IFN score/IFNλ1 ratio seems to be a potential marker of high risk APS given its associations with triple aPL positivity.
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Affiliation(s)
- Christina-Maria Flessa
- Department of Physiology, National and Kapodistrian University of Athens, Athens, Greece; First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stelios Vlachiotis
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Adrianos Nezos
- Department of Physiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Clio P Mavragani
- Department of Physiology, National and Kapodistrian University of Athens, Athens, Greece; Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria G Tektonidou
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, Athens, Greece.
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28
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NETosis is associated with the severity of aortic stenosis: Links with inflammation. Int J Cardiol 2019; 286:121-126. [DOI: 10.1016/j.ijcard.2019.03.047] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 03/18/2019] [Accepted: 03/24/2019] [Indexed: 12/19/2022]
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29
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El-Ghoneimy DH, Hesham M, Hasan R, Tarif M, Gouda S. The behavior of neutrophil extracellular traps and NADPH oxidative activity in pediatric systemic lupus erythematosus: relation to disease activity and lupus nephritis. Clin Rheumatol 2019; 38:2585-2593. [PMID: 31030361 DOI: 10.1007/s10067-019-04547-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/01/2019] [Accepted: 04/03/2019] [Indexed: 12/23/2022]
Abstract
OBJECTIVES To evaluate the neutrophil extracellular traps (NETs) assay and NADPH oxidase (Nox2) activity in pediatric systemic lupus erythematosus (pSLE) in relation to each other and SLE characteristics. METHODS This cross-sectional study included 50 children and adolescents with pSLE who were clinically evaluated and underwent routine laboratory work up of SLE (CBC, ESR, 24 hrs urinary proteins, serum creatinine, complement-3 (C3), anti-dsDNA, and antiphospholipid antibodies). NETs assay and dihydrorhodamine (DHR) test were done for patient group and 50 age- and sex-matched control group. RESULTS The level of NETs was found significantly elevated among the patients (median 74.6 mU/ml) as compared to the controls (median 8.9 mU/ml) (p < 0.001), while values of DHR test were comparable between patients (median 95.5%) and controls (median 96.1%) (P = 0.55). There was a significant negative correlation between levels of NETs and DHR (p < 0.001). A significant positive correlation was noted between the 24 hrs urinary protein and NETs level (p < 0.001), but a significant negative correlation with DHR (p < 0.0001). Both NETs and DHR test values did not differ significantly between classes of lupus nephritis. NETs showed a significant positive correlation with anti-dsDNA titer (p = 0.004) and SLEDAI (p < 0.001), but a negative correlation with C3 (p < 0.001). DHR test was positively correlated with C3 levels (p = 0.003), but negatively correlated with anti-dsDNA titers (p = 0.008) and SLEDAI (p < 0.001). CONCLUSION NETs seem to have strong association with biomarkers of pSLE activity. On the other hand, Nox2 activity of the neutrophils was noted to be linked to quiescent state of SLE. KEY POINTS • Neutrophils have displayed different actions in pSLE through the NETs and Nox2 activity. • The inverse correlation between NETs and Nox2 activity makes the later a non-fundamental pathway for NETs formation. • NETs are associated with pSLE flare and LN activity, while neutrophil Nox2 activity is related to disease remission.
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Affiliation(s)
- Dalia Helmy El-Ghoneimy
- Pediatric Allergy and Immunology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt.
| | - Mohamed Hesham
- Pediatric Allergy and Immunology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt
| | - Rasha Hasan
- Pediatric Allergy and Immunology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt
| | - Mohamed Tarif
- Department of Clinical Pathology, Ain Shams University, Cairo, Egypt
| | - Sally Gouda
- Pediatric Allergy and Immunology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt
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30
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Neutrophils: back in the thrombosis spotlight. Blood 2019; 133:2186-2197. [PMID: 30898858 DOI: 10.1182/blood-2018-10-862243] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 12/14/2018] [Indexed: 12/11/2022] Open
Abstract
Reactive and clonal neutrophil expansion has been associated with thrombosis, suggesting that neutrophils play a role in this process. However, although there is no doubt that activated monocytes trigger coagulation in a tissue factor-dependent manner, it remains uncertain whether stimulated neutrophils can also directly activate coagulation. After more than a decade of debate, it is now largely accepted that normal human neutrophils do not synthetize tissue factor, the initiator of the extrinsic pathway of coagulation. However, neutrophils may passively acquire tissue factor from monocytes. Recently, the contact system, which initiates coagulation via the intrinsic pathway, has been implicated in the pathogenesis of thrombosis. After the recent description of neutrophil extracellular trap (NET) release by activated neutrophils, some animal models of thrombosis have demonstrated that coagulation may be enhanced by direct NET-dependent activation of the contact system. However, there is currently no consensus on how to assess or quantify NETosis in vivo, and other experimental animal models have failed to demonstrate a role for neutrophils in thrombogenesis. Nevertheless, it is likely that NETs can serve to localize other circulating coagulation components and can also promote vessel occlusion independent of fibrin formation. This article provides a critical appraisal of the possible roles of neutrophils in thrombosis and highlights some existing knowledge gaps regarding the procoagulant activities of neutrophil-derived extracellular chromatin and its molecular components. A better understanding of these mechanisms could guide future approaches to prevent and/or treat thrombosis.
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31
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You Y, Liu Y, Li F, Mu F, Zha C. Anti-β2GPI/β2GPI induces human neutrophils to generate NETs by relying on ROS. Cell Biochem Funct 2019; 37:56-61. [PMID: 30701573 PMCID: PMC6590372 DOI: 10.1002/cbf.3363] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/27/2018] [Accepted: 10/16/2018] [Indexed: 12/28/2022]
Abstract
Neutrophils participate in the regulation of pathogens by phagocytosis as well as by generating neutrophil extracellular traps (NETs). Antiphospholipid antibodies, particularly those targeting beta-2-glycoprotein I (β2GPI), stimulate monocytes, platelets, and endothelial cells with prothrombotic participation. This study aimed to explore NET generation in response to anti-β2GPI/β2GPI. A series of experiments involving the separation of primary human leukocytes, NETosis quantification using propidium iodide, exploration of NETosis by fluorescence microscopy, western blotting, examination of free Zn2+ using FluoZin-3, and reactive oxygen species (ROS) examination with dihydrorhodamine 123 were performed in this study. We found that anti-β2GPI/β2GPI triggered NETosis, resembling phorbol 12-myristate 13-acetate (PMA)-induced NETosis in magnitude and morphology. The anti-β2 GPI/β2 GPI complex in isolation stimulated NETs without relying on p38, protein kinase B (AKT), extracellular signal-related kinase (ERK) 1/2, and zinc signals. NET generation was unaffected by the NADPH oxidase suppressor DP1. The anti-β2 GPI/β2 GPI complex stimulated ROS generation without relying on NADPH oxidase, which may participate in NET generation triggered via the anti-β2 GPI/β2 GPI complex. In summary, our results indicate that the anti-β2 GPI/β2 GPI complex reinforced NET generation by relying on ROS. THE SIGNIFICANCE OF THE PAPER IN THE CONTEXT OF CURRENT KNOWLEDGE: Neutrophils as one of the first lines of defence and essential in the response to pathogen invasion. They eradicate bacteria via phagocytosis or by releasing antimicrobial proteins in degranulation. In this study, we explored the capability of anti-β2 GPI/β2 GPI to stimulate NETosis, demonstrating that anti-β2 GPI/β2 GPI is a promising method for triggering NET. Anti-β2 GPI/β2 GPI induced ROS generation without relying on NADPH oxidase, which contributes to NETosis independently of ERK1/2, Zn2+ , or AKT. Our results showed that anti-β2GPI/β2GPI triggered NETosis, resembling PMA-induced NETosis in magnitude as well as morphology. The anti-β2 GPI/β2 GPI complex in isolation stimulated NETs without relying on p38, AKT, ERK1/2, or zinc signals. The anti-β2 GPI/β2 GPI complex stimulated ROS generation without relying on NADPH oxidase, which may participate in NET generation triggered via the anti-β2 GPI/β2 GPI complex.
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Affiliation(s)
- Yanqiu You
- Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanhong Liu
- Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fujun Li
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fengyun Mu
- Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Caijun Zha
- Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Metz AK, Diaz JA, Obi AT, Wakefield TW, Myers DD, Henke PK. Venous Thrombosis and Post-Thrombotic Syndrome: From Novel Biomarkers to Biology. Methodist Debakey Cardiovasc J 2019; 14:173-181. [PMID: 30410646 DOI: 10.14797/mdcj-14-3-173] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Deep vein thrombosis (DVT) is a common disease that carries serious ramifications for patients, including pulmonary embolism and post-thrombotic syndrome (PTS). Although standard treatment for DVT is anticoagulation, this carries an added risk of bleeding and increased medication monitoring. Identifying those at risk for DVT and PTS can be difficult, and current research with murine models is helping to illuminate the biologic changes associated with these two disorders. Potential novel biomarkers for improving the diagnosis of DVT and PTS include ICAM-1, P-selectin, and cell-free DNA. Inhibition of factor XI, P- and E-selectin, and neutrophil extracellular traps holds promise for novel clinical treatment of DVT. Experimental research on PTS suggests potential cellular and mediator therapy targets of TLR9, MMP-2 and-9, PAI-1, and IL-6. Although many important concepts and mechanisms have been elucidated through research on DVT and PTS, more work must be done to translate experimental findings to the clinical arena. This review examines the currently used murine models of DVT, biomarkers involved in the pathophysiology and diagnosis of DVT and PTS, and potential pharmacologic targets for PTS treatment.
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Reyes-García AMDL, Aroca A, Arroyo AB, García-Barbera N, Vicente V, González-Conejero R, Martínez C. Neutrophil extracellular trap components increase the expression of coagulation factors. Biomed Rep 2019; 10:195-201. [PMID: 30906549 DOI: 10.3892/br.2019.1187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 11/29/2018] [Indexed: 12/22/2022] Open
Abstract
Neutrophil extracellular traps (NETs) represent an important link between inflammation and thrombosis. Here, the present study aimed to investigate the influence of the NET components, DNA and histone H4, on hemostatic gene expression. A further aim was to confirm the influence of H4 on the expression of tissue factor (TF) and investigate a potential effect of DNA, and to test the involvement of miR-17/92 and its paralog miR-106b-25 in this regulation. In HepG2 cells, the mRNA levels of factor VII and factor XII, which are crucial in the activation of the coagulation cascade, and of serpin family F member 2 (encoding α2-antiplasmin) were significantly upregulated by DNA and H4; while the mRNA levels of factor V, which is essential for thrombin generation of protein S, a cofactor of protein C that also has the ability to inhibit the factor X activation pathway, and of serpin family C member 1 (encoding antithrombin, the main endogenous anticoagulant) were significantly upregulated only by H4. H4 and DNA also provoked an increase in hepatocyte nuclear factor 4α (HNF4A) mRNA expression that could be responsible for the increase in the expression of certain coagulant factors. In THP-1 cells, it was also demonstrated that H4 caused an increase in TF mRNA while decreasing several of the microRNAs (miRNA/miRs) of the cluster miR-17/92, which may in part explain the increase in the expression of TF. The present results suggest the ability of NET components to alter the hemostatic balance and a possible involvement of HNF4α and miRNAs in this regulation.
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Affiliation(s)
- Ascensión María de Los Reyes-García
- Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain
| | - Alejandra Aroca
- Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain
| | - Ana Belén Arroyo
- Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain
| | - Nuria García-Barbera
- Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain
| | - Vicente Vicente
- Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain
| | - Rocío González-Conejero
- Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain
| | - Constantino Martínez
- Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain
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Jin Q, Kant S, Alhariri J, Geetha D. Levamisole adulterated cocaine associated ANCA vasculitis: review of literature and update on pathogenesis. J Community Hosp Intern Med Perspect 2018; 8:339-344. [PMID: 30559941 PMCID: PMC6292360 DOI: 10.1080/20009666.2018.1536242] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 10/09/2018] [Indexed: 12/27/2022] Open
Abstract
Levamisole is an antihelminth drug and a common cocaine contaminant, present in an estimated 71% of cocaine samples in the US. Levamisole-contaminated cocaine has been linked to an ANCA-associated vasculitis with cutaneous, renal, and pulmonary manifestations. We report the case of a 46 year old woman with known cocaine exposure who presents with recurrent, large purpuric and maculopapular rash of the extremities and face and review existing cases of levamisole/cocaine-associated ANCA vasculitis, We summarize the clinical presentation, treatment, and outcomes of levamisole induced vasculitis. There is emerging research on pathogenesis relating to neutrophil extracellular traps (NETs). We review studies implicating role of NETs in the pathogenesis of levamisole induced vasculitis. Further research to explore the use of NETs as therapeutic targets in drug induced vasculitis is needed.
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Affiliation(s)
- Qiuyu Jin
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sam Kant
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA
| | - Jihad Alhariri
- Division of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Duvuru Geetha
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Zamora-Medina MDC, Hinojosa-Azaola A, Nuñez-Alvarez CA, Vargas-Ruiz AG, Romero-Diaz J. Anti-RNP/Sm antibodies in patients with systemic lupus erythematosus and its role in thrombosis: a case-control study. Clin Rheumatol 2018; 38:885-893. [PMID: 30515663 DOI: 10.1007/s10067-018-4381-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 11/22/2018] [Accepted: 11/26/2018] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To validate the association of thrombotic events with positive lupus anticoagulant (LA) and co-presence of anti-RNP/Sm, as well as the diagnostic accuracy of this combination of antibodies for thrombosis. METHODS Case-control study of patients with systemic lupus erythematosus (SLE) who presented thrombosis after SLE diagnosis and controls with SLE without thrombosis. Comorbidities, traditional risk factors, clinical variables, and treatment were evaluated. Antiphospholipid (aPL) and anti-RNP/Sm antibodies were determined. RESULTS Sixty-three cases and 63 controls were studied, 88% women, median age of 40 years, and disease duration of 135 months at study inclusion. No differences were found between groups regarding age, comorbidities, or clinical characteristics at SLE diagnosis. Patients with thrombosis were more frequently positive for anti-RNP/Sm (p = 0.001), IgG aCL (p = 0.02), IgG anti-B2GPI (p = 0.02), IgM anti-B2GPI (p = 0.02), LA (p < 0.001), the combination of anti-RNP/Sm + LA (p < 0.001), and aPL triple marker (p = 0.002), compared to controls. The combination of anti-RNP/Sm + LA, SLEDAI-2 K, and prednisone dose was associated with thrombosis (p < 0.05). The combination of anti-RNP/Sm + LA showed 56% sensitivity, 79% specificity, 73% positive predictive value, 64% negative predictive value, positive likelihood ratio (LR) 2.69, and negative LR 0.56 for predicting thrombosis. No difference was found in the comparison of area under the curve between LA alone and the combination of anti-RNP/Sm + LA (p = 0.73). CONCLUSION Thrombosis was associated with disease activity, dose of prednisone, and the combination of anti-RNP/Sm antibodies and LA. This combination of antibodies could be useful in the identification of SLE patients at risk of thrombosis.
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Affiliation(s)
- María Del Carmen Zamora-Medina
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Col. Sección XVI, Tlalpan, 14000, Mexico City, Mexico
| | - Andrea Hinojosa-Azaola
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Col. Sección XVI, Tlalpan, 14000, Mexico City, Mexico
| | - Carlos A Nuñez-Alvarez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Col. Sección XVI, Tlalpan, 14000, Mexico City, Mexico
| | - Angel Gabriel Vargas-Ruiz
- Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Juanita Romero-Diaz
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Col. Sección XVI, Tlalpan, 14000, Mexico City, Mexico.
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Antiphospholipid antibodies in adult IgA vasculitis: observational study. Clin Rheumatol 2018; 38:347-351. [PMID: 30073461 DOI: 10.1007/s10067-018-4248-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/11/2018] [Accepted: 07/27/2018] [Indexed: 01/10/2023]
Abstract
We evaluated the occurrence of antiphospholipid antibodies (aPLs) in acute adult IgA vasculitis (IgAV), and potential correlations with IgAV clinical presentation. We determined lupus anticoagulants (LAs) and IgG, IgM, and IgA isotypes of anticardiolipin antibodies (aCL), antibodies against β2-glycoprotein I (aβ2GPI) and against the phosphatidylserine-prothrombin complex (aPS/PT) in prospectively collected, histologically proven IgAV, diagnosed for the first time between January 2013 and February 2018 at our secondary/tertiary rheumatology center. During the 62 months, we determined aPLs in 125 IgAV patients (56.8% male; median (IQR) age 64.7 (48.6-78.2) years). Sixty-four (51.2%) patients had aPLs. We found LAs, aPS/PT, aβ2GPI, and aCL in 24.8%, 21.6%, 13.6%, and 11.2% of cases, respectively. With 17.6%, the IgA aPS/PT was the most common aPL subtype. aPL-positive and aPL-negative patients did not differ in the clinical presentation of acute IgAV or in the frequency of thrombotic events. aPL-positive IgAV patients had significantly higher erythrocyte sedimentation rate (p < 0.001), and C-reactive protein (p < 0.001). The subset of IgA aPS/PT-positive patients more commonly had renal involvement in acute disease (RR 2.4 (95% CI 1.6-3.7)). aPLs are commonly detected during acute IgAV episodes. Patients with aPLs have similar clinical presentation, but higher markers of inflammation at than those without them. The subset of IgAV patients with IgA aPS/PT more commonly had renal involvement.
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Yalavarthi S, Knight JS. Reply. Arthritis Rheumatol 2018; 68:1321-2. [PMID: 26748667 DOI: 10.1002/art.39579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 12/31/2015] [Indexed: 11/10/2022]
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Turrent-Carriles A, Herrera-Félix JP, Amigo MC. Renal Involvement in Antiphospholipid Syndrome. Front Immunol 2018; 9:1008. [PMID: 29867982 PMCID: PMC5966534 DOI: 10.3389/fimmu.2018.01008] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 04/23/2018] [Indexed: 12/13/2022] Open
Abstract
Antiphospholipid syndrome is a complex autoimmune disease, characterized by the presence of vascular thrombosis, obstetric, hematologic, cutaneous, and cardiac manifestations. Renal disease in patients with antiphospholipid syndrome was not recognized in the first descriptions of the disease, but later on, the renal manifestations of the syndrome have been investigated widely. Renal manifestations of antiphospholipid syndrome conform a wide spectrum of diverse renal syndromes. Hypertension is one of the most frequent, but less commonly recognized renal alteration. It can be difficult to control as its origin is renovascular. Renal vascular thrombosis can be arterial or venous. Other alterations are renal infarction and vascular thrombosis in arterial territories. Venous thrombosis can be present in primary and secondary antiphospholipid syndrome; it presents with worsening of previous proteinuria or de novo nephrotic syndrome, hypertension and renal failure. Antiphospholipid syndrome nephropathy is a vascular disease that affects glomerular tuft, interstitial vessels, and peritubular vessels; histopathology characterizes the renal lesions as acute or chronic, the classic finding is thrombotic microangiopathy, that leads to fibrosis, tubule thyroidization, focal cortical atrophy, and glomerular sclerosis. Antiphospholipid syndrome nephropathy can also complicate patients with systemic lupus erythematosus, and there is vast information supporting the worse renal prognosis in this group of patients with the classic histopathologic lesions. Treatment consists of anticoagulation, as for other thrombotic manifestations of antiphospholipid syndrome. There is some evidence of glomerulonephritis as an isolated lesion in patients with antiphospholipid syndrome. The most frequently reported glomerulonephritis is membranous; with some reports suggesting that immunosuppressive treatment may be effective. Patients with end stage renal disease commonly are positive for antiphospholipid antibodies, but it is not clear what is the role of aPL in this setting. Patients with vascular access may have complications in the presence of antibodies so that anticoagulation is recommended. Patients ongoing renal transplant with persistent antiphospholipid antibody positivity may have early and late graft failure.
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Affiliation(s)
| | | | - Mary-Carmen Amigo
- Internal Medicine Rheumatology Service, Centro Médico ABC, Mexico City, Mexico
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Duan J, Liang S, Yu Y, Li Y, Wang L, Wu Z, Chen Y, Miller MR, Sun Z. Inflammation-coagulation response and thrombotic effects induced by silica nanoparticles in zebrafish embryos. Nanotoxicology 2018; 12:470-484. [PMID: 29658397 PMCID: PMC6157531 DOI: 10.1080/17435390.2018.1461267] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Nowadays, nanotechnology environmental health and safety (nanoEHS) is gaining attention. We previously found that silica nanoparticles (SiNPs) could induce vascular endothelial damage. However, the subsequent toxicologic response to SiNPs-induced endothelial damage was still largely unknown. In this study, we explored the inflammation–coagulation response and thrombotic effects of SiNPs in endothelial cells and zebrafish embryos. For in vitro study, swollen mitochondria and autophagosome were observed in ultrastructural analysis. The cytoskeleton organization was disrupted by SiNPs in vascular endothelial cells. The release of proinflammatory and procoagulant cytokines including IL-6, IL-8, MCP-1, PECAM-1, TF and vWF, were markedly elevated in a dose-dependent manner. For in vivo study, based on the NOAEL for dosimetry selection, and using two transgenic zebrafish, Tg(mpo:GFP) and Tg(fli-1:EGFP), SiNPs-induced neutrophil-mediated inflammation and impaired vascular endothelial cells. With the dosage higher than NOAEL, SiNPs significantly decreased blood flow and velocity, exhibiting a blood hypercoagulable state in zebrafish embryos. The thrombotic effect was assessed by o-dianisidine staining, showed that an increasing of erythrocyte aggregation occurred in SiNPs-treated zebrafish. Microarray analysis was used to screen the possible genes for inflammation–coagulation response to SiNPs in zebrafish, and the JAK1/TF signaling pathway was further verified by qRT-PCR and Western blot assays. For in-deepth study, il6st was knocked down with specific morpholinos. The whole-mount in situ hybridization and qRT-PCR analysis showed that the expression jak1 and f3b were attenuated in il6st knockdown groups. In summary, our data demonstrated that SiNPs could induce inflammation–coagulation response and thrombotic effects via JAK1/TF signaling pathway.
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Affiliation(s)
- Junchao Duan
- a Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , P.R. China.,b Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing , P.R. China
| | - Shuang Liang
- a Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , P.R. China.,b Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing , P.R. China
| | - Yang Yu
- a Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , P.R. China.,b Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing , P.R. China
| | - Yang Li
- a Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , P.R. China.,b Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing , P.R. China
| | - Lijing Wang
- a Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , P.R. China.,b Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing , P.R. China
| | - Zehao Wu
- a Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , P.R. China.,b Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing , P.R. China
| | - Yueyue Chen
- a Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , P.R. China.,b Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing , P.R. China
| | - Mark R Miller
- c BHF Centre for Cardiovascular Science, Queens Medical Research Institute, The University of Edinburgh , Edinburgh , UK
| | - Zhiwei Sun
- a Department of Toxicology and Sanitary Chemistry, School of Public Health , Capital Medical University , Beijing , P.R. China.,b Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing , P.R. China
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Abstract
PURPOSE OF REVIEW Antiphospholipid syndrome (APS) is a leading acquired cause of thrombosis and pregnancy loss. Upon diagnosis (which is unlikely to be made until at least one morbid event has occurred), anticoagulant medications are typically prescribed in an attempt to prevent future events. This approach is not uniformly effective and does not prevent associated autoimmune and inflammatory complications. The goal of this review is to update clinicians and scientists on mechanistic and clinically relevant studies from the past 18 months, which have especially focused on inflammatory aspects of APS pathophysiology. RECENT FINDINGS How antiphospholipid antibodies leverage receptors and signaling pathways to activate cells is being increasingly defined. Although established mediators of disease pathogenesis (like endothelial cells and the complement system) continue to receive intensive study, emerging concepts (such as the role of neutrophils) are also receiving increasing attention. In-vivo animal studies and small clinical trials are demonstrating how repurposed medications (hydroxychloroquine, statins, and rivaroxaban) may have clinical benefit in APS, with these concepts importantly supported by mechanistic data. SUMMARY As anticoagulant medications are not uniformly effective and do not comprehensively target the underlying pathophysiology of APS, there is a continued need to reveal the inflammatory aspects of APS, which may be modulated by novel and repurposed therapies.
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Knight JS, Meng H, Coit P, Yalavarthi S, Sule G, Gandhi AA, Grenn RC, Mazza LF, Ali RA, Renauer P, Wren JD, Bockenstedt PL, Wang H, Eitzman DT, Sawalha AH. Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target. JCI Insight 2017; 2:93897. [PMID: 28931754 DOI: 10.1172/jci.insight.93897] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 08/15/2017] [Indexed: 01/05/2023] Open
Abstract
Antiphospholipid antibodies, present in one-third of lupus patients, increase the risk of thrombosis. We recently reported a key role for neutrophils - neutrophil extracellular traps (NETs), in particular - in the thrombotic events that define antiphospholipid syndrome (APS). To further elucidate the role of neutrophils in APS, we performed a comprehensive transcriptome analysis of neutrophils isolated from patients with primary APS. Moreover, APS-associated venous thrombosis was modeled by treating mice with IgG prepared from APS patients, followed by partial restriction of blood flow through the inferior vena cava. In patients, APS neutrophils demonstrated a proinflammatory signature with overexpression of genes relevant to IFN signaling, cellular defense, and intercellular adhesion. For in vivo studies, we focused on P-selectin glycoprotein ligand-1 (PSGL-1), a key adhesion molecule overexpressed in APS neutrophils. The introduction of APS IgG (as compared with control IgG) markedly potentiated thrombosis in WT mice, but not PSGL-1-KOs. PSGL-1 deficiency was also associated with reduced leukocyte vessel wall adhesion and NET formation. The thrombosis phenotype was restored in PSGL-1-deficient mice by infusion of WT neutrophils, while an anti-PSGL-1 monoclonal antibody inhibited APS IgG-mediated thrombosis in WT mice. PSGL-1 represents a potential therapeutic target in APS.
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Affiliation(s)
- Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - He Meng
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Patrick Coit
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Srilakshmi Yalavarthi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Gautam Sule
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Alex A Gandhi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Robert C Grenn
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Levi F Mazza
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Ramadan A Ali
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Paul Renauer
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jonathan D Wren
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.,Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | | | - Hui Wang
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Daniel T Eitzman
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Amr H Sawalha
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.,Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
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An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med 2017; 23:279-287. [PMID: 28267716 DOI: 10.1038/nm.4294] [Citation(s) in RCA: 852] [Impact Index Per Article: 106.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 01/25/2017] [Indexed: 12/12/2022]
Abstract
The production of neutrophil extracellular traps (NETs) is a process that enables neutrophils to help catch and kill bacteria. However, increasing evidence suggests that this process might also occur in noninfectious, sterile inflammation. In this Review, we describe the role of NETosis in autoimmunity, coagulation, acute injuries and cancer, and discuss NETs as potential therapeutic targets. Furthermore, we consider whether extracellular DNA is always detrimental in sterile inflammation and whether the source is always NETs.
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Meng H, Yalavarthi S, Kanthi Y, Mazza LF, Elfline MA, Luke CE, Pinsky DJ, Henke PK, Knight JS. In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody-Mediated Venous Thrombosis. Arthritis Rheumatol 2017; 69:655-667. [PMID: 27696751 DOI: 10.1002/art.39938] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 09/15/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Antiphospholipid syndrome (APS) is a leading acquired cause of thrombotic events. Although antiphospholipid antibodies have been shown to promote thrombosis in mice, the role of neutrophils has not been explicitly studied. The aim of this study was to characterize neutrophils in the context of a new model of antiphospholipid antibody-mediated venous thrombosis. METHODS Mice were administered fractions of IgG obtained from patients with APS. At the same time, blood flow through the inferior vena cava was reduced by induction of stenosis. Resulting thrombi were characterized for size and neutrophil content. Circulating factors and the vessel wall were also assessed. RESULTS As measured by both thrombus weight and thrombosis frequency, mice treated with IgG from patients with APS (APS IgG) demonstrated exaggerated thrombosis as compared with control IgG-treated mice. Thrombi in mice treated with APS IgG were enriched for citrullinated histone H3 (a marker of neutrophil extracellular traps [NETs]). APS IgG-treated mice also demonstrated elevated levels of circulating cell-free DNA and human IgG bound to the neutrophil surface. In contrast, circulating neutrophil numbers and markers of vessel wall activation were not appreciably different between APS IgG-treated mice and control mice. Treatment with either DNase (which dissolves NETs) or a neutrophil-depleting antibody reduced thrombosis in APS IgG-treated mice to the level in control mice. CONCLUSION These data support a mechanism whereby circulating neutrophils are primed by antiphospholipid antibodies to accelerate thrombosis. This line of investigation suggests new, immunomodulatory approaches for the treatment of APS.
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Affiliation(s)
- He Meng
- University of Michigan Medical School, Ann Arbor
| | | | - Yogendra Kanthi
- University of Michigan Medical School and Ann Arbor Veterans Administration Healthcare System, Ann Arbor
| | - Levi F Mazza
- University of Michigan Medical School, Ann Arbor
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Bravo-Barrera J, Kourilovitch M, Galarza-Maldonado C. Neutrophil Extracellular Traps, Antiphospholipid Antibodies and Treatment. Antibodies (Basel) 2017; 6:antib6010004. [PMID: 31548520 PMCID: PMC6698875 DOI: 10.3390/antib6010004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Revised: 03/01/2017] [Accepted: 03/01/2017] [Indexed: 12/22/2022] Open
Abstract
Neutrophil extracellular traps (NETs) are a network of extracellular fibers, compounds of chromatin, neutrophil DNA and histones, which are covered with antimicrobial enzymes with granular components. Autophagy and the production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are essential in the formation of NETs. There is increasing evidence that suggests that autoantibodies against beta-2-glycoprotein-1 (B2GP1) induce NETs and enhance thrombosis. Past research on new mechanisms of thrombosis formation in antiphospholipid syndrome (APS) has elucidated the pharmacokinetics of the most common medication in the treatment of the disease.
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Affiliation(s)
- Jessica Bravo-Barrera
- UNERA (Unit of Rheumatic and Autoimmune Diseases), Hospital Monte Sinaí, Miguel Cordero 6-111 y av. Solano, Cuenca, Ecuador.
- Department of Hematology and Hemostasis, CDB, Hospital Clinic, Villaroel 170, 08036 Barcelona, Catalonia, Spain.
| | - Maria Kourilovitch
- UNERA (Unit of Rheumatic and Autoimmune Diseases), Hospital Monte Sinaí, Miguel Cordero 6-111 y av. Solano, Cuenca, Ecuador.
- Faculty of Medicine and Health Science, Doctorate Programme "Medicine and Translational Research", Barcelona University, Casanova, 143, 08036 Barcelona, Catalonia, Spain.
| | - Claudio Galarza-Maldonado
- UNERA (Unit of Rheumatic and Autoimmune Diseases), Hospital Monte Sinaí, Miguel Cordero 6-111 y av. Solano, Cuenca, Ecuador.
- Department of Investigation (DIUC-Dirección de Investigación de Universidad de Cuenca), Cuenca State University, Av. 12 de Abril y Agustin Cueva, Cuenca, Ecuador.
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Wang Y, Golden JB, Fritz Y, Zhang X, Diaconu D, Camhi MI, Gao H, Dawes SM, Xing X, Ganesh SK, Gudjonsson JE, Simon DI, McCormick TS, Ward NL. Interleukin 6 regulates psoriasiform inflammation-associated thrombosis. JCI Insight 2016; 1:e89384. [PMID: 27942589 DOI: 10.1172/jci.insight.89384] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Psoriasis patients are at increased risk of heart attack and stroke and have elevated MRP8/14 levels that predict heart attack. The KC-Tie2 psoriasiform mouse model exhibits elevated MRP8/14 and is prothrombotic. Mrp14-/- mice, in contrast, are protected from thrombosis, but, surprisingly, KC-Tie2xMrp14-/- mice remain prothrombotic. Treating KC-Tie2xMrp14-/- mice with anti-IL-23p19 antibodies reversed the skin inflammation, improved thrombosis, and decreased IL-6. In comparison, IL-6 deletion from KC-Tie2 animals improved thrombosis despite sustained skin inflammation, suggesting that thrombosis improvements following IL-23 inhibition occur secondary to IL-6 decreases. Psoriasis patient skin has elevated IL-6 and IL-6 receptor is present in human coronary atheroma, supporting a link between skin and distant vessel disease in patient tissue. Together, these results identify a critical role for skin-derived IL-6 linking skin inflammation with thrombosis, and shows that in the absence of IL-6 the connection between skin inflammation and thrombosis comorbidities is severed.
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Affiliation(s)
- Yunmei Wang
- Division of Cardiovascular Medicine, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA
| | - Jackelyn B Golden
- Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Yi Fritz
- Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Xiufen Zhang
- Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Doina Diaconu
- Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Maya I Camhi
- Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Huiyun Gao
- Division of Cardiovascular Medicine, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA
| | - Sean M Dawes
- Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA
| | | | - Santhi K Ganesh
- Department of Internal Medicine, Division of Cardiovascular Medicine, and Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Daniel I Simon
- Division of Cardiovascular Medicine, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA
| | - Thomas S McCormick
- Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Nicole L Ward
- Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA
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Kazzaz NM, Sule G, Knight JS. Intercellular Interactions as Regulators of NETosis. Front Immunol 2016; 7:453. [PMID: 27895638 PMCID: PMC5107827 DOI: 10.3389/fimmu.2016.00453] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 10/11/2016] [Indexed: 12/12/2022] Open
Abstract
Neutrophil extracellular traps (NETs) are chromatin-derived webs extruded from neutrophils in response to either infection or sterile stimulation with chemicals, cytokines, or microbial products. The vast majority of studies have characterized NET release (also called NETosis) in pure neutrophil cultures in vitro. The situation is surely more complex in vivo as neutrophils constantly sample not only pathogens and soluble mediators but also signals from cellular partners, including platelets and endothelial cells. This complexity is beginning to be explored by studies utilizing in vitro co-culture, as well as animal models of sepsis, infective endocarditis, lung injury, and thrombosis. Indeed, various selectins, integrins, and surface glycoproteins have been implicated in platelet–neutrophil interactions that promote NETosis, albeit with disparate results across studies. NETosis can also clearly be regulated by soluble mediators derived from platelets, such as eicosanoids, chemokines, and alarmins. Beyond platelets, the role of the endothelium in modulating NETosis is being increasingly revealed, with adhesive interactions likely priming neutrophils toward NETosis. The fact that the same selectins and surface glycoproteins may be expressed by both platelets and endothelial cells complicates the interpretation of in vivo data. In summary, we suggest in this review that the engagement of neutrophils with activated cellular partners provides an important in vivo signal or “hit” toward NETosis. Studies should, therefore, increasingly consider the triumvirate of neutrophils, platelets, and the endothelium when exploring NETosis, especially in disease states.
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Affiliation(s)
- Nayef M Kazzaz
- Department of Internal Medicine, Division of Rheumatology, University of Michigan , Ann Arbor, MI , USA
| | - Gautam Sule
- Department of Internal Medicine, Division of Rheumatology, University of Michigan , Ann Arbor, MI , USA
| | - Jason S Knight
- Department of Internal Medicine, Division of Rheumatology, University of Michigan , Ann Arbor, MI , USA
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Feuring M, van Ryn J. The discovery of dabigatran etexilate for the treatment of venous thrombosis. Expert Opin Drug Discov 2016; 11:717-31. [DOI: 10.1080/17460441.2016.1188077] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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Marder W, Knight JS, Kaplan MJ, Somers EC, Zhang X, O'Dell AA, Padmanabhan V, Lieberman RW. Placental histology and neutrophil extracellular traps in lupus and pre-eclampsia pregnancies. Lupus Sci Med 2016; 3:e000134. [PMID: 27158525 PMCID: PMC4854113 DOI: 10.1136/lupus-2015-000134] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 03/18/2016] [Accepted: 03/28/2016] [Indexed: 12/12/2022]
Abstract
Objective Systemic lupus erythematosus (SLE) is associated with increased risk of adverse pregnancy outcomes, including pre-eclampsia, particularly in association with antiphospholipid antibody syndrome (APS). While significant placental abnormalities are expected in pre-eclampsia, less is known about how lupus activity and APS in pregnancy affect the placenta. We describe placental pathology from a population of lupus pregnancies, several of which were complicated by APS-related thromboses, in which pre-eclampsia and other complications developed. We performed standard histopathological placental review and quantified neutrophils and neutrophil extracellular traps (NETs) in the intervillous space, given the recognised association of NETs with lupus, APS and pre-eclampsia. Methods Pre-eclampsia, SLE and control placentas were scored for histological features, and neutrophils were quantified on H&E and immunohistochemical staining for the granular protein myeloperoxidase. NETs were identified by extracellular myeloperoxidase staining in the setting of decondensed nuclei. Non-parametric analysis was used to evaluate differences in netting and intact neutrophils between groups, with Kruskal–Wallis testing for associations between histological findings and neutrophils. Results Placentas were evaluated from 35 pregnancies: 10 controls, 11 pre-eclampsia, 4 SLE+pre-eclampsia and 10 SLE, including one complicated by catastrophic APS and one complicated by hepatic and splenic vein thromboses during pregnancy. Intrauterine growth restriction and oligohydramnios were observed in lupus cases but not controls. Significantly more NETs were found infiltrating placental intervillous spaces in pre-eclampsia, SLE+pre-eclampsia and all 10 SLE non-pre-eclampsia cases. The ratio of NETs to total neutrophils was significantly increased in all case groups compared with controls. When present, NETs were associated with maternal vasculitis, laminar decidual necrosis, maternal–fetal interface haemorrhage and non-occlusive fetal thrombotic vasculopathy. Conclusions In this pilot study of placental tissue from lupus pregnancies, outcomes were more complicated, particularly if associated with APS. Placental tissue revealed marked inflammatory and vascular changes that were essentially indistinguishable from placental tissue of pre-eclampsia pregnancies.
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Affiliation(s)
- Wendy Marder
- Division of Rheumatology, Department of Internal Medicine,University of Michigan, Ann Arbor, Michigan, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan , USA
| | - Mariana J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, Maryland , USA
| | - Emily C Somers
- Division of Rheumatology, Department of Internal Medicine,University of Michigan, Ann Arbor, Michigan, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA; Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA
| | - Xu Zhang
- Division of Rheumatology, Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan , USA
| | - Alexander A O'Dell
- Division of Rheumatology, Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan , USA
| | - Vasantha Padmanabhan
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | - Richard W Lieberman
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
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Thieblemont N, Wright HL, Edwards SW, Witko-Sarsat V. Human neutrophils in auto-immunity. Semin Immunol 2016; 28:159-73. [DOI: 10.1016/j.smim.2016.03.004] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 03/08/2016] [Accepted: 03/12/2016] [Indexed: 01/06/2023]
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