NLRP3炎症小体在心房颤动中的作用的研究进展

心房颤动(房颤)的发病率与日俱增,尽管在过去二十年中,房颤的治疗手段日新月异,但房颤患者的致残率、致死率仍居高不下。因此,需继续探索房颤的新型治疗靶点,从而造福患者。炎症反应在房颤的发生发展过程中发挥着重要的作用。近年来,核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎症小体在心血管疾病中的作用引起越来越多学者的关注。多项研究证实NLRP3炎症小体与房颤关系密切,但其机制尚不清楚,深入阐明NLRP3炎症小体与房颤的关系,对房颤的防治具有重要意义。现就NLRP3炎症小体与房颤的关系及其机制的研究进展做一综述。     

黄连温胆汤调控NLRP3炎症小体抗动脉粥样硬化机制

目的 观察黄连温胆汤抗ApoE-/-小鼠动脉粥样硬化的干预效应,从核苷酸结合寡聚化结构域样受体蛋白(NLRP)3炎症小体途径探讨其作用机制。方法 采用高脂饲料饲养ApoE-/-小鼠建立动脉粥样硬化模型,随机分为模型对照组、黄连温胆汤低剂量组[9 g/(kg·d)]、黄连温胆汤中剂量组[18 g/(kg·d)]、黄连温胆汤高剂量组[36 g/(kg·d)],C57BL/6J小鼠作为正常对照组,灌胃给予相应药物4 w;采用全自动生化分析仪检测小鼠血清总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)水平;采用苏木素-伊红(HE)染色观察主动脉病理形态;采用酶联免疫吸附试验(ELISA)检测血清炎症因子白细胞介素(IL)-1β、IL-18水平;采用免疫组化法检测主动脉NLRP3、Caspase-1蛋白表达水平。结果 与模型对照组比较,黄连温胆汤高剂量组血清TC显著降低(P<0.05),黄连温胆汤中、高剂量组血清LDL-C显著降低(P<0.05);HE染色显示模型组主动脉根部斑块呈易损斑块特征,各给药组斑块趋于稳定;黄连温胆汤中、...     

炎症及NLRP3炎性小体在肺动脉高压中的作用研究进展

肺动脉高压是以肺动脉压力进行性升高为主要特征的肺血管疾病,可导致右心衰竭甚至死亡,目前尚无特效药。近年医学界发现炎症参与了肺动脉高压的发生、发展,其中NLRP3炎性小体作为启动固有免疫应答的关键炎症信号平台有望成为人们系统性认识肺动脉高压炎症性质的蛋白复合物,也可能是治疗的潜在靶点。本文就炎症及NLRP3炎性小体在肺动脉高压中的作用进行综述。     

NLRP3炎症小体在缺血再灌注损伤中的作用研究进展

缺血再灌注损伤是指器官在手术或外伤中遭受缺血打击,血流恢复再通后进一步加重器官损伤.炎症反应是引起缺血再灌注主要损伤之一,特别是NLRP3炎症小体引起的炎症级联反应,主导各器官缺血再灌注炎症损伤.近几年研究表明可通过抑制炎症小体改善缺血再灌注损伤.本文对NLRP3炎症小体在重要器官缺血再灌注损伤中的作用研究进行综述.     

NLRP3炎症小体在海水吸入性急性肺损伤中的表达和作用

目的探讨海水吸入型急性肺损伤大鼠肺组织中NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体表达的变化及介导的炎性因子在急性肺损伤(ALI)发生发展中的作用。 方法将50只健康雄性SD大鼠随机分为5组,对照组,海水吸入1 h组,海水吸入3 h组,海水吸入6 h组,海水吸入9 h组,每组10只。采用经气管缓慢滴注(3 ml/kg)海水的方法制作大鼠损伤模型。制作大鼠肺脏石蜡切片并HE染色观察病理形态学变化。检测大鼠肺组织湿干比。ELISA检测测定各组肺组织中IL-1β和IL-18水平,RT-PCR检测肺组织中IL-1β、IL-18和NLRP3mRNA的表达。Western-blot检测肺组织中NLRP3蛋白表达。 结果气管滴注海水后成功复制海水吸入性急性肺损伤模型。肺组织湿干比较对照组显著升高。病理形态学观察可见肺组织大量炎细胞浸润、水肿、间质增厚。各组大鼠血清中IL-1β和IL-18的水平随着时间增加逐渐升高,且在3～6 h达到顶峰,随后炎症因子的表达逐渐降低。与空白对照组比较,差异均有统计学意义(均P<0.05)。各组大鼠肺组织中IL-1β和IL-18的mRNA的表达水平与大鼠肺组织中IL-1β和IL-18的表达基本一致。与空白对照组比较,差异均有统计学意义(均P<0.05)。肺组织匀浆中NLRP3转录和翻译结果显示海水吸入刺激后,肺组织中NLRP3的mRNA和NLRP3蛋白含量变化含量随着时间明显逐渐增加,差异均有统计学意义(均P<0.05)。 结论海水刺激下,NLRP3炎症小体介导的炎症反应参与了急性肺损伤发病过程并加重了肺损伤的程度,可能是海水急性肺损伤的发病机制之一,但其作用有待进一步证实。     

NLRP3炎症小体及其激活产物在慢性阻塞性肺疾病中的作用研究进展

慢性阻塞性肺疾病(COPD)是一种常见的以持续气流受限为特征的疾病,与气道和肺对有毒颗粒或气体的慢性炎症反应增强有关.COPD发病率、致死率高,造成了严重的经济和社会负担.然而迄今为止,没有一种治疗COPD的药物可以有效地阻止疾病的进展.目前认为,气道和肺部的慢性炎症是导致COPD发生发展的主要机制.然而促使炎症产生并大量扩散的机制尚不清楚.炎症小体最近被发现在呼吸系统疾病的炎症发生发展中发挥重要作用.种种证据表明香烟烟雾导致NLRP3炎症小体的活化,促使IL-1β和IL-18的成熟和释放增多,可能在COPD的慢性炎症中发挥重要作用,为临床上治疗COPD提供了新的思路.     

NLRP3炎症小体与阿尔茨海默病研究进展

<正>阿尔茨海默病(AD)典型病理变化为脑区神经细胞间出现大量老年斑(SP),神经元胞体中出现神经元纤维缠结(NFTs),神经元丢失及胶质细胞增生等〔1〕。β-淀粉样蛋白(Aβ)假说已经成为AD发病机制的主流学说。一方面,Aβ可引起Tau蛋白异常磷酸化,进而导致DNA损伤、钙离子(Ca2+)内流、氧化应激等变化,推进AD神经退行性变进程〔2〕。另一方面,病理性Aβ沉积还可通过激活钙通道触发内质网及线粒体应激反应引起细胞凋亡、突触完整性破坏和细胞膜功能丧失,导致记忆能力下降和认知功能障碍〔3〕。     

NLRP3炎症小体在糖尿病相关认知障碍发病中的作用及相应治疗研究进展

糖尿病相关认知障碍（DACI）是指糖尿病患者伴有认知功能损害,该类患者自我管理能力不足、血糖控制水平欠佳,预后不良。核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎症小体作为炎症反应和先天免疫系统的核心,其激活后通过抑制自噬、诱导神经炎症和细胞焦亡、破坏血脑屏障、引起线粒体功能障碍和内质网应激等多种途径参与DACI的发生和发展。基础研究发现,降糖药物、中药和靶向药物等通过抑制NLRP3炎症小体可有效干预DACI。但由于缺乏临床试验,针对NLRP3炎症小体的治疗尚未在临床应用。     

NLRP3炎性小体在心脏重构中的作用和进展

心脏重构是多重因素下所致的心脏结构和功能受损,炎症在心脏重构发生发展中起了重要作用,干预炎症有望成为新的治疗靶点,NLRP3炎性小体在心脏炎症中起了主导作用,本文通过概述NLRP3炎性小体在心脏重构中的作用,深入探讨其潜在的机制,以望给临床带来更多的策略。     

AMPK信号通路和NLRP3炎症小体在肝衰竭中的研究进展

肝衰竭是由多种因素导致的严重肝脏结构和功能损伤,且是一个涉及“三重打击”的复杂病理生理过程。在机体内,AMPK信号在调节细胞能量平衡中起着重要作用。肝脏作为机体的代谢工厂,对能量的产生和利用有着严格的调控。此外,NLRP3炎症小体也在众多炎症性疾病发生发展过程中扮演着重要角色。而AMPK信号通路和NLRP3小体之间存在交互影响。本文就AMPK介导的多种信号通路、NLRP3炎症小体的激活效应及二者之间的相互作用在肝衰竭过程中的研究进展做一综述。     

核苷酸结合寡聚化结构域样受体蛋白3炎性小体抑制剂

NLRP3炎性小体是由核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain,NOD)样受体蛋白3(Nod-like receptor protein3,NLRP3)、凋亡相关斑点样蛋白(apoptosis associated speck-like protein containing CARD,ASC)及无活性的半胱氨酸天冬氨酸蛋白酶1(cysteine-requiring asparate protease-1,caspase-1)前体组成的复合体。已有多项实验研究证实NLRP3炎性小体的活化是各种危险因素激活机体炎症反应的关键环节,NLRP3炎性小体参与到了多种疾病的发生发展过程中,如2型糖尿病、冠状动脉粥样硬化、痛风、NLRP3相关自身炎症性疾病、阿尔兹海默病、炎性肠病等。研发靶向调控NLRP3炎性小体的药物为治疗此类炎症代谢性疾病提供了新的思路。本文对近年来NLRP3炎性小体抑制剂的研究进展进行综述。     

Role of NLRP3 inflammasome in inflammatory bowel diseases

Inflammasomes are multiprotein intracellular complexes which are responsible for the activation of inflammatory responses. Among various subtypes of inflammasomes, NLRP3 has been a subject of intensive investigation. NLRP3 is considered to be a sensor of microbial and other danger signals and plays a crucial role in mucosal immune responses, promoting the maturation of proinflammatory cytokines interleukin 1β(IL-1β) and IL-18. NLRP3 inflammasome has been associated with a variety of inflammatory and autoimmune conditions, including inflammatory bowel diseases(IBD). The role of NLRP3 in IBD is not yet fully elucidated as it seems to demonstrate both pathogenic and protective effects. Studies have shown a relationship between genetic variants and mutations in NLRP3 gene with IBD pathogenesis. A complex interaction between the NLRP3 inflammasome and the mucosal immune response has been reported. Activation of the inflammasome is a key function mediated by the innate immune response and in parallel the signaling through IL-1β and IL-18 is implicated in adaptive immunity. Further research is needed to delineate the precise mechanisms of NLRP3 function in regulating immune responses. Targeting NLRP3 inflammasome and its downstream signaling will provide new insights into the development of future therapeutic strategies.     

NLRP3炎症小体与肺部疾病

NLRP3炎症小体是细胞内固有免疫系统的感受器,是-类通过活化caspase-1来间接调控IL-18与IL-18的成熟和分泌的蛋白复合体。作为机体固有免疫及应激系统的重要防御成分,NLRP3炎症小体参与了多种疾病发生和进展。近年发现NLRP3炎症小体与肺部疾病关系密切。本文就NLRP3炎症小体的组成、活化机制及其在肺炎、肺结核、COPD及哮喘等肺部疾病中的研究作一综述。     

瓜蒌-薤白对ApoE－/－小鼠动脉粥样硬化过程中NLRP3炎症小体活化的影响

目的通过建立ApoE^-/-小鼠动脉粥样硬化(As)模型,探讨As病程不同时间点NOD样受体热蛋白结构域3(NLRP3)炎症小体表达水平的变化及瓜蒌-薤白的干预作用。方法将高脂饲养6、20、34周的ApoE^-/-小鼠均随机分为模型组(M1、M2、M3)和给药组[6 g/(kg·d)](GX1、GX2、GX3),每组10只;另设C57BL/6J小鼠为空白组(C1、C2、C3)。空白组及模型组小鼠给予生理盐水灌胃,给药组小鼠每日给予相应药物灌胃,共4周。实验结束后处死小鼠,油红O染色评估主动脉斑块面积及形态;HE染色观察主动脉病理形态学变化;免疫组织化学法检测主动脉NLRP3表达;ELISA法检测血清中白细胞介素1β(IL-1β)和白细胞介素18(IL-18)水平;Western blot法检测主动脉组织中NLRP3、凋亡相关斑点样蛋白(ASC)、含半胱氨酸的天冬氨酸蛋白水解酶1(Caspase-1)的蛋白表达;qRT-PCR检测主动脉组织中NLRP3、ASC、Caspase-1的mRNA表达。结果在As病程进展过程中,模型组小鼠主动脉脂质累积和斑块面积显著增加,血清中IL-1β和IL-18的表达不断升高,NLRP3和ASC的蛋白及mRNA的表达均不断上调。Caspase-1的蛋白表达也呈上升趋势,但M2与M3组间的比较无统计学差异。与模型组相比,给药组各时间点小鼠主动脉的脂质累积和斑块面积显著减少,血清中IL-1β和IL-18的水平降低;主动脉组织中N LRP3、ASC、Caspase-1蛋白和mRNA表达显著下调。结论NLRP3炎症小体参与了主动脉As的病变过程,瓜蒌-薤白可能通过调节As模型小鼠主动脉不同阶段NLRP3炎症小体的表达,从而发挥抗As的作用。     

Role of NLRP3 inflammasome in liver disease

Inflammasomes have become an important natural sensor of host immunity, and can protect various organs against pathogenic infections, metabolic syndromes, cellular stress and cancer metastasis. Inflammasomes are intracellular multi‐protein complexes found in both parenchymal and non‐parenchymal cells, stimulating the initiation of caspase‐1 and interleukin (IL)‐1β and IL‐18 in response to cell danger signals. Inflammasomes induce cell death mechanisms. The potential role of NOD‐like receptor protein 3 (NLRP3) inflammasome in alcoholic and non‐alcoholic steatohepatitis, hepatitis, nanoparticle‐induced liver injury and other liver diseases has recently attracted widespread attention from clinicians and researchers. In this review we summarize the role played by the NLRP3 inflammasome in molecular and pathophysiological mechanisms in the pathogenesis and progression of liver disease. This article aims to establish that targeting the NLRP3 inflammasome and other inflammasome components may make a significant therapeutic approach to the treatment of liver disease.     

Human NLRP3 inflammasome senses multiple types of bacterial RNAs

Inflammasomes are multiprotein platforms that activate caspase-1, which leads to the processing and secretion of the proinflammatory cytokines IL-1β and IL-18. Previous studies demonstrated that bacterial RNAs activate the nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome in both human and murine macrophages. Interestingly, only mRNA, but neither tRNA nor rRNAs, derived from bacteria could activate the murine Nlrp3 inflammasome. Here, we report that all three types of bacterially derived RNA (mRNA, tRNA, and rRNAs) were capable of activating the NLRP3 inflammasome in human macrophages. Bacterial RNA’s 5′-end triphosphate moieties, secondary structure, and double-stranded structure were dispensable; small fragments of bacterial RNA were sufficient to activate the inflammasome. In addition, we also found that 20-guanosine ssRNA can activate the NLRP3 inflammasome in human macrophages but not in murine macrophages. Therefore, human and murine macrophages may have evolved to recognize bacterial cytosolic RNA differently during bacterial infections.The innate immune system is the first line of defense against microbial infections. Germ-line–encoded pattern-recognition receptors (PRRs) of the innate immune system recognize the presence of invariant evolutionarily conserved microbial components called “pathogen-associated molecular patterns” (1–3). In response to microbial infections, PRRs rapidly initiate signal-transduction pathways to induce type 1 IFN production, proinflammatory cytokine production, and inflammasome activation. The inflammasome is a cytosolic large caspase-1–containing multiprotein complex that enables autocatalytic activation of caspase-1. Once caspase-1 is activated, it starts to cleave prointerleukin-1β (pro–IL-1β) and prointerleukin-18 (pro–IL-18) proteolytically into bioactive IL-1β and IL-18 (4–7). The mature forms of IL-1β and IL-18 play roles in a variety of infectious and inflammatory processes.Cytosolic microbial nucleic acids are important activators of the innate immune system against both bacterial and viral infections, which induce type 1-IFN and proinflammatory cytokine responses as well as inflammasome activation. The role of microbial nucleic acids in inflammasome activation has been studied mostly in murine bone marrow-derived dendritic cells (BMDCs) or bone marrow-derived macrophages (BMDMs). AIM2 has been identified as a specific cytosolic dsDNA sensor that directly binds ASC (apoptosis-associated speck-like protein containing a carboxyl-terminal CARD-like domain) and forms inflammasome complexes in human and murine cells (8–11).Viral dsRNA was found to activate the nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome in human and murine cells (12–15). Several groups have reported that cytosolic bacterial RNA activate the Nlrp3 inflammasome in murine macrophages (13, 16, 17). Our group also has reported that human THP-1–derived macrophages recognize cytosolic bacterial RNA and induce NLRP3 inflammasome activation (12). Bacterial RNA is composed of mRNA, tRNA, and three different sizes of rRNA (23s, 16s, and 5s). Sander et al. (18) reported that, of the different types of Escherichia coli RNA, only E. coli mRNA induced the secretion of IL-1β by murine BMDMs, but E. coli tRNA and E. coli rRNAs did not.We aimed to study (i) whether a variety of cytosolic bacterial RNAs could activate the inflammasome in human myeloid cells and (ii) what types of bacterial RNA activate the inflammasome in human and murine myeloid cells. Here, we demonstrate that a broad spectrum of cytosolic bacterial RNAs strongly induce the cleavage of caspase-1 and the secretion of IL-1β and IL-18 in human macrophages. Human macrophages can sense mRNA, tRNA, rRNAs, and small synthetic ssRNA through NLRP3, but murine macrophages can sense only the mRNA component. Bacterial RNA’s 5′-end triphosphate moieties, secondary structure, and double-stranded structure were dispensable, but small fragments of bacterial RNA were sufficient to activate the inflammasome. These findings suggest that upon bacterial infections the human and murine NLRP3 inflammasomes sense cytosolic bacterial RNAs differently.     

固有免疫介导的炎症反应在动脉粥样硬化发病机制中的研究进展

动脉粥样硬化是常见慢性心脑血管疾病的病理基础,其病变始于血管内皮细胞构成的天然屏障功能障碍,由各种损伤因子影响内皮细胞Caspase-1/Sirt1/AP-1、SREBP2/NOX2/NLRP3、KLF2/FoxP1/NLRP3、NFAT5/NLRP3等通路信号转导、相关炎症基因表达,激活内皮细胞,继而单核细胞浸润主动脉壁内膜下并分化为巨噬细胞,引起相应内皮激活的固有免疫反应,在NLRP3/ASC/Caspase-1炎性小体途径激活后,使促炎症细胞因子IL-1β、IL-18释放增加,介导下游炎症因子、趋化因子等表达增加,促进动脉粥样硬化炎症反应;血管壁持续慢性炎症反应使血管平滑肌细胞表型转变,促进动脉粥样硬化斑块形成,还使斑块成分发生改变、易损性增加,斑块微钙化则增加了斑块处血管应力,破裂危险增加。本文综述了固有免疫介导的动脉粥样硬化炎症机制研究现状,为动脉粥样硬化抗炎药物研发提供思路以及促进抗动脉粥样硬化研究的实验设计。     

病毒感染与NLRP3炎性小体

炎性小体是一类由多蛋白组成的复合物,通常由NOD样受体蛋白家族(NLRs)、凋亡相关斑点样蛋白(ASC)及半胱氨酸天冬氨酸蛋白酶-1(caspase-1)组成,是固有免疫系统的一个重要组成部分。机体受到刺激(内源性刺激或外源性刺激),启动炎性小体的激活,caspase-1活化,进而促使下游炎性因子(IL-18、IL-1β)成熟与分泌来参与炎症的发生及发展。近年来研究最为广泛的是NLRP3炎性小体。本文就NLRP3炎性小体的结构、激活及在病毒感染时NLRP3炎性小体的激活与调控作一综述。