中性粒细胞胞外诱捕网在心血管疾病中的作用

心血管疾病目前被认为是多因素参与的慢性炎症性疾病,中性粒细胞作为机体防御系统的第一道防线,广泛参与心血管疾病的发生发展。近期研究显示,作为先天性免疫吞噬细胞的中性粒细胞,可形成中性粒细胞胞外诱捕网(neutrophil extracellular traps,NETs)促进免疫反应的发展及持续,从而在心血管疾病中发挥重要调控作用。本综述详述了中性粒细胞和NETs在心血管疾病进展中的作用,并讨论了将NETs作为潜在治疗靶点的可能性。     

病原体逃逸中性粒细胞胞外诱捕网机制

中性粒细胞胞外诱捕网（NETs）是新发现的中性粒细胞抗病原机制,是天然免疫系统的重要组成部分。但病原体在进化中形成了针对NETs的免疫逃逸机制。不同的病原体逃逸NET的机制不同,本文主要介绍3种机制：降解NETs-DNA、表面分子机制和NETosis调控。     

中性粒细胞胞外诱捕网与子痫前期

子痫前期与母体先天免疫系统过度激活有关.激活的循环中性粒细胞形成细胞外诱捕网(neutrophil extracellular traps,NETs).NETs由染色质-DNA、抗微生物肽和抗微生物酶构成,具有捕获与杀灭微生物的作用.中性粒细胞形成NETs是先天免疫应答机制之一.胎盘衍生因子IL-8和合体滋养细胞微粒激活循环中性粒细胞并产生NETs.子痫前期NETs含量增加提示NETs与子痫前期病因有关.     

中性粒细胞胞外诱捕网与肺部炎症性疾病的关系

中性粒细胞募集/浸润是肺部炎症性疾病的特征性表现,是肺部抵抗病原微生物入侵的第一道防线,主要通过吞噬作用杀灭病原微生物.然而,新近的研究发现,中性粒细胞被刺激后可形成一种以DNA为骨架并镶嵌有大量活性蛋白质的网状物质——中性粒细胞胞外诱捕网(neutrophil extracellular traps,NETs),这种特殊形式的生物结构能捕获并杀灭病原微生物.尽管就NETs的生物学功能而言,其对肺部炎症性疾病应该是有益的,但是越来越多的研究表明,NETs对肺上皮细胞和内皮细胞均具有直接的细胞毒性作用,并可能促进肺部炎症性疾病的发生发展.为了系统地了解NETs与肺部相关炎症性疾病的关系,本综述首先简述了NETs的结构、功能和形成过程,然后分别叙述了NETs与哮喘、慢性阻塞性肺病、细菌性肺炎、肺结核、肺囊性纤维化、间质性肺疾病、流感病毒感染和急性肺损伤的关系.最后总结、展望了NETs在肺部炎症性疾病中的潜在研究方向和针对性治疗策略.     

中性粒细胞胞外诱捕网和血栓形成的研究进展

中性粒细胞胞外诱捕网是由DNA骨架、组蛋白、颗粒成分以及胞浆蛋白组成的网状物,它通过捕获致病微生物,抑制其扩散、灭活毒力因子以及清除病原体来发挥抗菌活性,中性粒细胞这种与其经典的趋化、吞噬作用不同的胞外杀菌方式发挥着重要的固有免疫应答作用。然而,中性粒细胞胞外诱捕网的产生是一把双刃剑。近年来有研究表明它可以导致凝血异常、刺激血栓形成并为其提供支架,但这一过程的机制并不十分清楚,可能与中性粒细胞胞外诱捕网的促凝活性以及凝血级联反应的激活有关。本文将就中性粒细胞胞外诱捕网及其与血栓形成之间关系的研究进展做一综述。     

中性粒细胞胞外诱捕网在炎症相关疾病中的研究进展

中性粒细胞是抵御病原体入侵机体的第一道防线,通过趋化和吞噬作用使病原体失活,从而进行免疫防御,杀灭病原体。研究证实,中性粒细胞通过吞噬病原体、分泌抗微生物蛋白颗粒来杀灭病原微生物。2004年Brinkmann发现了一种中性粒细胞新型抗感染机制,即中性粒细胞经病原体活化刺激后释放中性粒细胞胞外诱捕网(neutrophil extracellular trap,NET)至细胞外。NET是由双链DNA染色质和镶嵌在染色质上的抗菌蛋白构成的纤维网格状结构,通过网罗、捕获而杀灭病原体。诸多研究表明,NET在炎症相关疾病中起重要作用,其生成和降解会影响急慢性炎性疾病的病理过程。本文主要从NET的特征、产生机制、抗菌作用及其在炎性相关疾病中的作用等方面着手,概述其最新研究进展,为炎性疾病的治疗及其药物开发提供新的思路和方向。     

中性粒细胞胞外诱捕网在相关疾病中的作用

中性粒细胞胞外诱捕网(neutrophil extracellular traps,NETs)是中性粒细胞在受到特殊因素影响后释放到细胞外的一种纤维网状复合物。在病毒、细胞因子、活化血小板、补体、自身抗体等因子的诱导下,特定的中性粒细胞亚群产生并释放NETs,NETs在体内发挥多种作用,参与心血管疾病、代谢性疾病、自身免疫性疾病等多种疾病的发展,也与相关非感染性病理过程如凝血障碍、血栓形成、动脉粥样硬化、血管炎等有密切关系。因而在相关疾病中控制NETs的发生和发展可能是潜在的疾病治疗靶点。该文总结了NETs在代谢性疾病、肿瘤和新型冠状病毒感染等相关疾病中的影响,探讨了抗NETs药物的临床应用,以期为临床药物选择和应用提供新思路。     

中性粒细胞胞外诱捕网(NETs)在肝细胞癌转移中的作用与机制研究

肝细胞癌(HCC)是一种炎症相关癌症,肿瘤免疫微环境在HCC的发生和发展中起关键作用。该文旨在研究中性粒细胞胞外诱捕网(NETs)在HCC转移中的作用及相关机制。ELISA和免疫组化方法检测HCC患者血清和肿瘤组织中的NETs水平以检测NETs与肝癌转移的相关性。在体外实验中,建立NETs与肝癌细胞系Hep3B和CSQT-2体外共培养模型,通过划痕实验和Transwell等实验,研究NETs对肝癌细胞迁移的影响。在体内实验中,建立尾静脉注射转移瘤模型并使用脂多糖诱导小鼠体内NETs形成,通过检测肝脏病理变化和肝脏Ki67蛋白水平等指标,研究NETs对肿瘤转移的作用。最后,为了探讨NETs影响HCC转移的机制,通过质谱的方法检测了NETs对细胞外基质的修饰,并检测了修饰的细胞外基质蛋白对整合素/FAK信号通路的影响。结果发现:高转移HCC患者肿瘤组织中髓过氧化物酶蛋白水平较高,且与早期HCC患者相比,晚期HCC患者血清中的MPO和中性粒细胞弹性蛋白酶水平升高。体外实验中, NETs与Hep3B和CSQT-2细胞共培养,可以促进Hep3B和CSQT-2细胞的迁移能力。体内实验中, NETs...     

细胞外诱捕网介导的抗微生物途径

活化中性粒细胞与肥大细胞在细胞外形成纤维样诱捕网结构（ETs）。ETs以染色质-DNA为骨架,吸附有抗微生物肽和抗微生物酶组成,具有捕获与杀灭微生物的作用。由ETs介导的抗微生物途径构成了一种重要的先天免疫应答机制。     

Regulating Neutrophil PAD4/NOX-Dependent Cerebrovasular Thromboinflammation

Background: Neutrophil extracellular trap (NET) production has been implicated in the pathogenesis of thromboinflammatory conditions such as Sickle Cell Disease (SCD), contributing to heightened risk for ischemic stroke. NETs are catalyzed by the enzyme Peptidyl Arginine Deiminase 4 (PAD4) and neutrophil derived reactive oxygen species (ROS), especially NADPH oxidase (NOX) which interacts with PAD4 and is therefore critical for neutrophil function. However, the role that NOX-dependent ROS and NETs play in the accelerated cerebral microvascular thrombosis associated with thromboinflammatory conditions, such as SCD, has not been fully elucidated and is the aim of this study.Methods: The in-vitro effects of targeting PAD4 and NOX were examined using physiologically relevant NET assays with neutrophils isolated from healthy volunteers (control) and SCD patients. In addition, in-vivo intravascular effects of targeting PAD4 and NOX in the cerebral microcirculation of C57BL/6 and sickle transgenic mice (STM) were assessed using a photoactivation thrombosis model (light/dye) coupled with real-time fluorescence intravital microscopy.Results: We found that targeting PAD4 and NOX in human neutrophils significantly inhibited ionomycin dependent H3cit⁺ neutrophils. Targeting PAD4 and NOX in-vivo resulted in prolonged blood flow cessation in cerebrovascular arterioles as well as venules. Moreover, we were able to replicate the effects of PAD4 and NOX targeting in a clinical model of accelerated thromboinflammation by increasing blood flow cessation times in cerebral microvessels in STM. These findings concurred with the clinical setting i.e. neutrophils isolated from SCD patients, which possessed an attenuation of H3cit⁺ neutrophil production on targeting PAD4 and NOX.Conclusions: Taken together, our compelling data suggests that PAD4 and NOX play a significant role in neutrophil driven thromboinflammation. Targeting PAD4 and NOX limits pathological H3cit⁺ neutrophils, which may further explain attenuation of cerebral thrombosis. Overall, this study presents a viable pre-clinical model of prevention and management of thromboinflammatory complications such as ischemic stroke.     

Peptidylarginine deiminase 4 concentration,but not PADI4 polymorphisms,is associated with ICU mortality in septic shock patients

The objective of our study was to evaluate the association between peptidylarginine deiminase 4 (PAD4) concentration and its polymorphisms with mortality in patients with septic shock . We prospectively evaluated 175 patients aged over 18 years with septic shock upon intensive care unit (ICU) admission. However, 48 patients were excluded. Thus, 127 patients were enrolled in the study. At the time of the patients’ enrollment, demographic information was recorded. Blood samples were taken within the first 24 hours of the patient's admission to determine serum PAD4 concentrations and its polymorphism PADI4_89 [rs11203366], PADI4_94 [rs2240340] and PADI4_104 [rs1748033]. The mean age was 63.3 ± 15.2 years, 56.7% were male, PAD4 concentration was 4.62 (2.48‐6.20) ng/mL and the ICU mortality rate was 67.7%. The patients who died in the ICU had higher APACHE II and Sequential Organ Failure Assessment (SOFA) scores. In addition, PAD4 concentration was higher in patients who died during ICU stay. However, there were no differences regarding PADI4 polymorphisms and ICU mortality. In the logistic regression models, PAD4 concentrations were associated with ICU mortality when adjusted for APACHE II score and lactate (OR: 1.477; CI 95%: 1.186‐1.839; P < .001), and when adjusted for age, gender and APACHE II score (OR: 1.392; CI 95%: 1.145‐1.692; P < .001). In conclusion, PAD4 concentration, but not PADI4_89, PADI4_94 and PADI4_104 polymorphisms, is associated with ICU mortality in septic shock patients.     

PAD4:一种治疗类风湿性关节炎的新靶酶

肽酰基精氨酸脱亚氨酶4(PAD4)催化肽酰精氨酸残基转变为肽酰瓜氨酸残基,其活性失调与类风湿性关节炎(RA)的发生与发展有关.目前PAD4被认为是开发新RA治疗药物的一种新靶酶.认识PAD4的结构与可能的作用机制,对于开发新RA治疗药物是重要的.     

中性粒细胞在肿瘤微环境、肿瘤发生发展及诊治中的作用

中性粒细胞是循环系统中最丰富的白细胞,是肿瘤微环境的重要组成部分.中性粒细胞参与肿瘤发生发展过程中的不同阶段,包括肿瘤的发生、增殖和转移.肿瘤微环境中的中性粒细胞群体表现出异质性表型和功能多样性,在肿瘤微环境中扮演促瘤或抑瘤双重角色.本综述重点阐述中性粒细胞在肿瘤微环境中的募集、异质性和极化性,在肿瘤发生发展中及其在临...     

Hookworms Evade Host Immunity by Secreting a Deoxyribonuclease to Degrade Neutrophil Extracellular Traps

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Interplay between neutrophils and trophoblast cells conditions trophoblast function and triggers vascular transformation signals

Normal placentation entails highly regulated interactions of maternal leukocytes with vascular and trophoblast cells to favor vascular transformation. Neutrophil activation and neutrophil extracellular trap (NET) formation associate with poor placentation and severe pregnancy complications. To deepen into the mechanisms of trophoblast–neutrophil interaction, we explored the effects of NETs on trophoblast cell function and, conversely, whether trophoblast cell-derived factors condition neutrophils to favor angiogenesis and anti-inflammatory signals required for fetal growth. NETs isolated from activated neutrophils hindered trophoblast cell migration. Trophoblast conditioned media prevented the effect as well as the vasoactive intestinal peptide (VIP) known to regulate trophoblast and neutrophil function. On the other hand, factors released by trophoblast cells and VIP shaped neutrophils to a proangiogenic profile with increased vascular endothelial growth factor synthesis and increased capacity to promote vascular transformation. Results presented here provide novel clues to reconstruct the interaction of trophoblast cells and neutrophils in vivo during placentation in humans.     

T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants

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