炎症小体在恶性血液病发病中的作用

<正>炎症小体是一类胞质内多蛋白复合体,组装后活化半胱氨酸天氰冬氨酸蛋白酶(caspase)-1,进而介导白细胞介素(IL)-1β、IL-18等细胞因子的成熟和释放。随着对炎症小体的深入研究,炎症小体除启动炎症反应外,也参与恶性肿瘤的发生、发展、转移及预后。炎症小体组分及其诱导产生细胞因子IL-1β、IL-18在不同恶性血液病中表达、作用及机制各异。本文就炎症小体与白血病、骨髓增生异常综合征(MDS)、多发性骨髓瘤     

炎症小体在结核分枝杆菌感染中的作用研究进展

炎症小体(inflammasome)是由应激,组织损伤和细胞内感染等途径激活的多蛋白复合物,它通过激活半胱天冬酶-1(caspase-1)从而促进IL-1β,IL-18等有效促炎细胞因子的释放,引起炎症反应和细胞焦亡。它是先天免疫中的一部分,和多种疾病相关,研究表示结核分枝杆菌感染巨噬细胞亦可激活NLRP3和AIM2炎症小体并引起炎症反应,本文就NLRP3炎症小体和AIM2炎症小体在结核分枝杆菌感染中的作用进展做一综述。     

胸膜渗液中细胞活素的含量(结核性与癌性胸膜炎的比较)

细胞活素包括白细胞介素1(IL-1)、IL-2和γ-干扰素(IFN-γ),是机体对各种感染,炎症和免疫应答反应的关键性调节物。IL-1在 T 细胞活化中具有重要作用,其生物学特性及在炎症中的关键作用表明,它们参与许多疾病的病理过程.IL-2在免疫反应调节中起决定性的作用.在分裂素或抗原活化后,它诱导和维持 T 细胞的增殖,诱导细胞毒性淋巴细胞、自然杀伤细胞和淋巴细胞活素活化的杀伤细胞产生。IFN-γ不但具有抗病毒和抗细胞的活性,而且还是一个重要的免疫调节剂.腺苷脱氨酶     

NLRP3炎症小体对炎症性肠病免疫机制影响的研究进展

炎症性肠病的发病与机体自身免疫内环境密切相关,而NLRP3炎症小体参与机体的固有免疫应答和T细胞免疫应答.慢性炎症阶段,典型的NLRP3炎症小体被过度激活,增加IL-1β和IL-18从固有层巨噬细胞和树突状细胞中的释放, IL-1β和IL-18的释放可诱导T细胞向致病性Th1和Th17的表型分化,从而维持炎症反应.急性期IL-1β主要以髓系细胞来源促进肠上皮细胞的愈合和修复,即NLRP3炎症小体对肠上皮细胞具有保护性的功能.而同时, NLRP3炎症小体介导的IL-1β的表达导致Th17/Treg失衡,这也与IBD的发病密切相关.可以说NLRP3作为肠内稳态的分子开关,通过IL-1β使局部免疫细胞向炎症表型转变.     

NOD样受体蛋白3炎症小体在非酒精性脂肪性肝炎中的作用

非酒精性脂肪性肝炎(NASH)是非酒精性脂肪性肝病的重要病理阶段,主要特征为肝细胞脂肪变性、肝损伤和炎症,可进一步发展为肝硬化和肝细胞癌。NOD样受体蛋白3(NLRP3)炎症小体是细胞内一种多蛋白复合体,可通过激活半胱氨酸天冬酶-1,释放成熟的IL-1β、IL-18等炎症因子,并诱导细胞焦亡,进而扩大炎症反应。近年来,研究发现NLRP3炎症小体可参与NASH的发生发展。概述了NLRP3炎症小体在NASH中的作用,为今后的相关研究及治疗提供理论基础。     

NLRP3炎症小体抑制剂在心血管疾病应用中的研究进展

NLRP3炎症小体是一类多聚蛋白复合物，可提供反应平台快速诱导对感染和无菌损伤的炎症反应。研究表明NLRP3炎症小体参与心血管事件发生发展，其抑制剂的研发已成为当前心血管疾病治疗领域研究热点。本文以NLRP3为切入点，总结NLRP3在心血管系统中激活机制、发挥的关键调控作用以及NLRP3炎症小体抑制剂最新研究进展，以期为NLRP3炎症小体为靶点的心血管疾病抗炎药物研发提供参考。     

炎症小体与肾脏疾病

炎症小体是细胞质中的一种复杂的蛋白,被认为是各种自身免疫疾病的调节因子,它可以诱导细胞活化、细胞因子及炎症介质释放,引起炎症反应,对固有免疫系统免疫功能的发挥具有重要的作用。近来研究表明,NLRP3炎症小体在肾脏疾病发病过程中发挥重要作用。本文就炎症小体与肾脏疾病关联作一综述,为以NLRP3为靶点治疗各种肾脏疾病提供新的治疗思路。     

NLRP3炎症小体与呼吸系统疾病

NLRP3炎症小体是一种存在于细胞胞浆中的多蛋白复合物,主要是由NLRP3、ASC和Caspase-1相互结合形成的,是天然免疫系统的重要组成部分。近来发现其在呼吸系统炎症的发生、发展过程中发挥着巨大的作用。本篇文章旨在讨论NLRP3炎症小体及其相关的炎症介质(IL-1β和IL-18)在哮喘和慢性阻塞性肺疾病发病机制中的重要作用。     

小鼠急性日本血吸虫病肝脏肉芽肿动态及脾细胞IL-4 mRNA水平的相应变化

本研究观察了小鼠急性日本血吸虫病肝脏肉芽肿的动态改变及在ConA或SEA体外诱导下小鼠脾细胞IL－4mRNA水平的相应变化。实验结果显示SEA刺激下牌细胞IL－4mRNA的动态变化与肝脏内芽肿的形成、发展及调节过程密切相关。在血吸虫成虫排卵前,无论ConA或SEA均不能诱导IL－4mRNA的转录。在感染后5周,肝脏肉芽肿开始出现．此时用RT－PCR法可以检测到IL－4mRNA的特异条带。感染后8周,肉芽肿炎症反应达高峰,SEA诱导的IL-4mRNA转录水平同时增高。感染10周以后,肉芽肿体积逐渐缩小,IL－4mRNA特异条带也同时消失。提示IL-4可能在肉芽肿的形成及调节过程中起重要作用。     

AIM2炎症小体在自身免疫性疾病发病中的作用研究进展

黑色素瘤缺乏因子2(AIM2)是AIM2炎症小体的重要组成部分。AIM2主要定位在细胞质中,与胞质中的双链DNA结合后,招募凋亡相关斑点样蛋白和半胱天冬酶1(Caspase-1)前体在内的凋亡相关蛋白,诱导Caspase依赖性的炎症小体形成,促使Caspase-1激活及IL-1β成熟与分泌,启动自身免疫反应。AIM2介导的免疫反应异常激活可导致免疫相关疾病,例如类风湿关节炎、系统性红斑狼疮、原发性干燥综合征、银屑病、白塞病等。在自身免疫疾病中,自身或外来DNA的异常累积可以激活AIM2炎症小体,释放致炎因子,参与炎症反应。因此,调控AIM2炎症小体活性,可发挥免疫保护作用,并阻止组织损伤及限制自身免疫反应。     

Influenza A Virus Infection Activates NLRP3 Inflammasome through Trans-Golgi Network Dispersion

The NLRP3 inflammasome consists of NLRP3, ASC, and pro-caspase-1 and is an important arm of the innate immune response against influenza A virus (IAV) infection. Upon infection, the inflammasome is activated, resulting in the production of IL-1β and IL-18, which recruits other immune cells to the site of infection. It has been suggested that in the presence of stress molecules such as nigericin, the trans-Golgi network (TGN) disperses into small puncta-like structures where NLRP3 is recruited and activated. Here, we investigated whether IAV infection could lead to TGN dispersion, whether dispersed TGN (dTGN) is responsible for NLRP3 inflammasome activation, and which viral protein is involved in this process. We showed that the IAV causes dTGN formation, which serves as one of the mechanisms of NLRP3 inflammasome activation in response to IAV infection. Furthermore, we generated a series of mutant IAVs that carry mutations in the M2 protein. We demonstrated the M2 proton channel activity, specifically His37 and Trp41 are pivotal for the dispersion of TGN, NLRP3 conformational change, and IL-1β induction. The results revealed a novel mechanism behind the activation and regulation of the NLRP3 inflammasome in IAV infection.     

Inflammasomes and SARS-CoV-2 Infection

SARS-CoV-2 is a new type of coronavirus that has caused worldwide pandemic. The disease induced by SARS-CoV-2 is called COVID-19. A majority of people with COVID-19 have relatively mild respiratory symptoms. However, a small percentage of COVID-19 patients develop a severe disease where multiple organs are affected. These severe forms of SARS-CoV-2 infections are associated with excessive production of pro-inflammatory cytokines, so called “cytokine storm”. Inflammasomes, which are protein complexes of the innate immune system orchestrate development of local and systemic inflammation during virus infection. Recent data suggest involvement of inflammasomes in severe COVID-19. Activation of inflammasome exerts two major effects: it activates caspase-1-mediated processing and secretion of pro-inflammatory cytokines IL-1β and IL-18, and induces inflammatory cell death, pyroptosis, via protein called gasdermin D. Here, we provide comprehensive review of current understanding of the activation and possible functions of different inflammasome structures during SARS-CoV-2 infection and compare that to response caused by influenza A virus. We also discuss how novel SARS-CoV-2 mRNA vaccines activate innate immune response, which is a prerequisite for the activation of protective adaptive immune response.     

Dhori virus (Orthomyxoviridae: Thogotovirus) infection of mice produces a disease and cytokine response pattern similar to that of highly virulent influenza A (H5N1) virus infection in humans

Mice infected with Dhori virus (DHOV) develop a fulminant, systemic, and uniformly fatal illness that has many of the clinical and pathologic findings seen in H5N1 influenza A virus infection. However, the role of host's immune response in DHOV infection remains unclear. In this study, the concentrations of 23 inflammatory cytokines and chemokines were measured in the liver, lungs, and sera of mice during the course of DHOV infection. Liver function, level of viremia, and hematologic response were also monitored. Infected animals exhibited significant leucopenia and lymphopenia, which directly correlated with the disease progression. High yields of infectious virus along with strikingly elevated expression of various inflammatory mediators, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage inflammatory protein (MIP)-1alpha, manocyte chemoattractant protein (MCP)-1, and interferon (IFN)-alpha, indicate that these responses play an important role in the observed disease and pathology. The overall clinical, pathologic, and immunologic responses of ICR mice to DHOV infection closely resemble those described for highly virulent influenza A virus infection in humans, thereby offering a realistic, safe, and alternative animal model for studying the pathogenesis and treatment of highly pathogenic avian influenza virus.     

Toll-like receptor-mediated activation of neutrophils by influenza A virus

Influenza virus infection of the respiratory tract is characterized by a neutrophil infiltrate accompanied by inflammatory cytokine and chemokine production. We and others have reported that Toll-like receptor (TLR) proteins are present on human neutrophils and that granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment enhances IL-8 (CXCL8) secretion in response to stimulation with TLR ligands. We demonstrate that influenza virus can induce IL-8 and other inflammatory cytokines from GM-CSF-primed human neutrophils. Using heat inactivation of influenza virus, we show that viral entry but not replication is required for cytokine induction. Furthermore, endosomal acidification and viral uncoating are necessary. Finally, using single-cell analysis of intracellular cytokine accumulation in neutrophils from knockout mice, we prove that TLR7 is essential for influenza viral recognition and inflammatory cytokine production by murine neutrophils. These studies demonstrate neutrophil activation by influenza virus and highlight the importance of TLR7 and TLR8 in that response.     

NLRP3炎性小体与心血管疾病的研究进展

炎性小体(inflammasome)是一种多蛋白复合物,主要由识别炎症的胞浆型模式识别受体(PRRs)、接头蛋白凋亡相关斑点样蛋白(ASC)和效应蛋白前半胱天冬酶-1(pro-caspase-1)三部分组成。炎性小体的激活过程中最主要的步骤是白细胞介素-1β(IL-1β)和白细胞介素-18(IL-18)等炎性因子的成熟和释放,从而引起炎症反应。在心血管疾病中,有关核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎性小体的研究最为广泛。诸多研究表明,心血管疾病的危险因素同样可以激活NLRP3炎性小体进而促进疾病的发展。本文就近年来对NLRP3炎性小体在动脉粥样硬化、心肌梗死、高血压等心血管疾病中的形成、激活及相关治疗等方面进行综述。     

NLRP3炎性小体在心肌重构中的研究进展

NLRP3炎性小体是一个重要的多蛋白信号平台,与炎症反应密切相关,可协调宿主抗菌防御,并通过激活caspase 1,使促炎因子成熟（如IL-1β和IL-18）,引起凋亡等病理改变。近年报道,组装并激活的NLRP3炎性小体与心血管疾病的多种危险因素（如高血压、糖尿病和肥胖等）密切相关,可能是这些疾病重要触发因素或者内源性调节体,并参与了心肌重构的病理过程,这为探索心肌重构治疗新策略奠定了基础。本篇综述概括了目前NLRP3炎性小体与心肌重构相关的研究。     

NLRP3炎性体在心肌梗死后心室重塑中的作用

NLRP3炎性体是一种细胞内多蛋白复合物,是无菌性炎症反应的关键介质,在心肌梗死（myocardial Infarction,MI）的病理生理机制中发挥重要作用。NLRP3炎性体可调节半胱氨酸蛋白酶（caspase-1）的激活,促进IL-1β等炎症因子产生,参与细胞程序性死亡。大量研究表明,抑制NLRP3炎性体可有效减轻MI后炎症反应,从而改善MI后心功能不全及心室重塑。因此,NLRP3炎性体可能是减少MI后心血管事件的发生及改善预后新的治疗靶点,本文就NLRP3炎性体在MI后心室重塑中的作用进行综述。     

Targeting the Linear Ubiquitin Assembly Complex to Modulate the Host Response and Improve Influenza A Virus Induced Lung Injury

Influenza virus infection is characterized by symptoms ranging from mild congestion and body aches to severe pulmonary edema and respiratory failure. While the majority of those exposed have minor symptoms and recover with little morbidity, an estimated 500,000 people succumb to IAV-related complications each year worldwide. In these severe cases, an exaggerated inflammatory response, known as “cytokine storm”, occurs which results in damage to the respiratory epithelial barrier and development of acute respiratory distress syndrome (ARDS). Data from retrospective human studies as well as experimental animal models of influenza virus infection highlight the fine line between an excessive and an inadequate immune response, where the host response must balance viral clearance with exuberant inflammation. Current pharmacological modulators of inflammation, including corticosteroids and statins, have not been successful in improving outcomes during influenza virus infection. We have reported that the amplitude of the inflammatory response is regulated by Linear Ubiquitin Assembly Complex (LUBAC) activity and that dampening of LUBAC activity is protective during severe influenza virus infection. Therapeutic modulation of LUBAC activity may be crucial to improve outcomes during severe influenza virus infection, as it functions as a molecular rheostat of the host response. Here we review the evidence for modulating inflammation to ameliorate influenza virus infection-induced lung injury, data on current anti-inflammatory strategies, and potential new avenues to target viral inflammation and improve outcomes.     

Nasal cytokine and chemokine responses in experimental influenza A virus infection: results of a placebo-controlled trial of intravenous zanamivir treatment.

The local immune response to influenza virus infection was characterized by determining cytokine and chemokine levels in serial nasal lavage fluid samples from 15 volunteers experimentally infected with influenza A/Texas/36/91 (H1N1). The study was part of a randomized double-blind placebo-controlled trial to determine the prophylactic effect of intravenous zanamivir (600 mg 2x/day for 5 days), a highly selective inhibitor of influenza A and B virus neuraminidases, on the clinical symptoms of influenza infection. Nasal lavage fluid levels of interleukin (IL)-6, tumor necrosis factor-alpha, interferon-gamma, IL-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1alpha and -1beta increased in response to influenza virus infection and correlated statistically with the magnitude and time course of the symptoms. Treatment with zanamivir prevented the infection and abrogated the local cytokine and chemokine responses. These results reveal a complex interplay of cytokines and chemokines in the development of symptoms and resolution of influenza.     

FMDV Leader Protein Interacts with the NACHT and LRR Domains of NLRP3 to Promote IL-1β Production

Foot-and-mouth disease virus (FMDV) infection causes inflammatory clinical symptoms, such as high fever and vesicular lesions, even death of animals. Interleukin-1β (IL-1β) is an inflammatory cytokine that plays an essential role in inflammatory responses against viral infection. The viruses have developed multiple strategies to induce the inflammatory responses, including regulation of IL-1β production. However, the molecular mechanism underlying the induction of IL-1β by FMDV remains not fully understood. Here, we found that FMDV robustly induced IL-1β production in macrophages and pigs. Infection of Casp-1 inhibitor-treated cells and NOD-, LRR- and pyrin domain-containing 3 (NLRP3)-knockdown cells indicated that NLRP3 is essential for FMDV-induced IL-1β secretion. More importantly, we found that FMDV L^pro associates with the NACHT and LRR domains of NLRP3 to promote NLRP3 inflammasome assembly and IL-1β secretion. Moreover, FMDV L^pro induces calcium influx and potassium efflux, which trigger NLRP3 activation. Our data revealed the mechanism underlying the activation of the NLRP3 inflammasome after FMDV L^pro expression, thus providing insights for the control of FMDV infection-induced inflammation.