NLRP3炎性小体在病毒性心肌炎患者中的水平及临床意义

目的:检测病毒性心肌炎(VMC)患者的核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎性小体水平,探讨其临床意义。方法:选择2014年1月~2018年12月入院的170例VMC患者为VMC组,同期50例健康体检者为健康对照组。根据VMC病情严重程度,患者被进一步分为轻度组(60例)、中度组(56例)和重度组(54例)。测量比较各组外周血NLRP3 mRNA、半胱氨酸天冬氨酸蛋白酶(Caspase)-1 mRNA、白介素(IL)-1β和IL-18水平,分析VMC患者外周血单个核细胞(PBMCs)NLRP3 mRNA水平与Caspase-1 mRNA、IL-1β和IL-18水平的相关性,并采用ROC曲线分析NLRP3对VMC严重程度的预测价值。结果:与健康对照组比较,VMC组外周血NLRP3 mRNA[(0.98±0.08)比(2.04±0.25)]、Caspase-1 mRNA[(1.02±0.20)比(1.88±0.31)]、IL-1β[(20.10±5.10)pg/ml比(41.63±6.50)pg/ml]和IL-18[(29.50±6.13)pg/ml比(36.80±8.70)pg/ml]水平均显著升高,P均=0.001。在不同严重程度的VMC亚组间,上述指标水平均符合:轻度组<中度组<重度组,两两比较均有显著差异,P均=0.001。Pearson相关分析显示VMC患者PBMCs NLRP3 mRNA水平与Caspase-1 mRNA、IL-1β和IL-18水平呈显著正相关(r=0.650~0.830,P均=0.001)。ROC曲线分析显示,外周血NLRP3水平的曲线下面积(AUC)为0.885(95%CI 0.806~0.965),最佳工作点(OOP)为1.66NLRP3/GAPDH amol/amol,以此OOP对VMC严重程度进行预测,其敏感性和特异性分别为86.36%和80.00%。结论:外周血NLRP3炎性小体与病毒性心肌炎的发生、发展密切相关,对其病情严重程度的预测,有一定的价值。     

肺炎支原体感染RAW264.7细胞NLRP3炎性体及下游分子的表达

目的观察肺炎支原体(Mycoplasma pneunoniae,Mp)感染RAW264.7细胞早期NLRP3炎性体及前炎性细胞因子的表达。方法将RAW264.7细胞随机分为5组,正常组用常规方法培养,不感染Mp;4个实验组RAW264.7细胞均用Mp感染4h,感染复数(细胞︰Mp)分别为1︰20、1︰40、1︰80、1︰100,采用FQ-PCR法检测细胞NLRP3、ASC、caspase-1mRNA表达和IL-1β、IL-18水平。结果 Mp感染复数1︰20、1︰40、1︰80、1︰100组NLRP3、ASC、caspase-1mRNA表达量分别为2.10±0.62、2.14±0.66、2.66±0.69、3.29±0.64和3.91±0.83、4.21±0.95、4.25±0.86、4.30±0.99和1.65±0.48、1.65±0.36、1.94±0.51、2.00±0.57,与正常对照组0.98±0.08、1.00±0.08、0.99±0.09比较,差异均有统计学意义(P<0.01);感染复数1︰100组IL-1β为200.00±9.25pg/ml,与对照组159.92±5.89pg/ml比较差异有统计学意义(P<0.01)。结论 Mp感染可诱导RAW264.7细胞NLRP3炎性体活化。NLRP3炎性体可能参与了Mp的早期感染。     

NLRP3炎性体与白细胞介素-1β在2型糖尿病中的作用

2型糖尿病是一种多基因遗传性、进展性疾病,2003年,糖尿病患者占世界总人口的2.8％,其中85％是2型糖尿病[1],严重威胁着人类的健康.因此,研究该病的发病机制,开发治疗该病更为有效的药物及方法迫在眉睫.2010年《科学》杂志发表了一篇题为NLRP3炎性体(NLRP3 inflammasome)在2型糖尿病中的主导作用为我们的研究提供了新的思路[2].NLRP3炎性体是什么,与白细胞介素-1β(IL-1β)有什么样的联系,在2型糖尿病的发生中有什么作用,本文对此进行了初步的研究.     

炎症小体与慢性肝脏疾病

多种慢性肝脏疾病都与组织的无菌性炎症有关。核苷酸结合寡聚化结构域样受体家族形成的多蛋白复合物——炎症小体,作为炎症反应的核心,能被多种外源或内源性刺激激活,引起下游炎症因子分泌,诱发炎症反应,其过度激活会造成组织损伤。现已证实炎症小体在酒精性和非酒精性脂肪性肝病、肝脏缺血再灌注损伤及药物性肝损伤等疾病中起关键作用,是肝脏发生纤维化和癌变的决定因素之一。本文就炎症小体的结构、活化信号及激活通路、调节机制及其与慢性肝脏疾病关系的研究进展作一综述,以期为慢性肝脏疾病的治疗提供新的方向和靶点。     

NLRP3炎性小体与冠心病的相关性

目的探讨核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎性小体与冠心病(CHD)的临床相关性。方法入选符合纳入标准的冠心病患者60例及对照者30例。收集所有研究对象的性别、年龄、吸烟史、体重指数(BMI)、平均动脉压(MAP)、空腹血糖(FPG)、糖化血红蛋白(Hb A1c)、血脂等临床资料,采用RT-q PCR、Western blot法分别检测各组外周血单个核细胞(PBMC)中NLRP3、凋亡相关微粒蛋白(ASC)、半胱氨酸蛋白酶1(Caspase-1)的mRNA及蛋白表达水平,ELISA法检测各组血浆中白细胞介素1β(IL-1β)、白细胞介素18(IL-18)水平。应用SPSS20.0软件进行统计分析。结果 PBMC中ASC mRNA、NLRP3、ASC、Caspase-1表达水平及血浆IL-1β、IL-18水平在冠心病组明显高于对照组(P0.05)。NLRP3、ASC、Caspase-1及其mRNA在各组分别进行Spearman相关分析显示,NLRP3 mRNA和Caspase-1 mRNA在冠心病组均与IL-18呈正相关(r分别为0.327和0.274,P0.05);ASC在冠心病组与年龄、IL-1β、IL-18呈正相关(r分别为0.370、0.467、0.403,P0.05);Caspase-1在冠心病组与吸烟、IL-18呈正相关(r分别为0.613和0.414,P0.05)。结论以NLRP3炎性小体为中心的NLRP3-ASC-Caspase-1-IL-1β/IL-18信号通路可能在冠心病的发生发展过程中发挥着重要作用。     

NLRP3炎性体加重小鼠脑缺血再灌注损伤的机制探讨

目的：探讨Nod样受体蛋白3（NLRP3）炎性体（NLRP3蛋白、IL-1β、IL-8）在小鼠脑缺血再灌注损伤中的作用和机制。方法将C57BL／6小鼠随机分为对照组和格列本脲（ NLRP3抑制剂）组各20只,每组中一半小鼠通过大脑中动脉栓塞法构建缺血再灌注（ IR）模型,其余接受假手术处理。格列本脲组术前30 min腹腔注射500 mg／kg格列本脲。造模成功后对小鼠进行神经学评分,2,3,5,-氯化三苯基四氮唑染色,并计算缺血梗死面积,HE染色观察病理变化,TUNEL染色观察各组神经元凋亡情况,Western Blot检测小鼠脑组织NLRP3蛋白表达,ELISA检测小鼠脑组织中IL-1β、IL-18浓度。结果各组IR小鼠脑损伤程度均重于假手术小鼠,但是对照组IR小鼠脑损伤程度比格列本脲组严重。 HE染色和TUNEL染色显示,IR小鼠脑组织出现明显损伤,神经元凋亡数量明显增多,格列本脲可减轻IR造成的病理损伤程度。与对照组相比,格列本脲组的脑组织NLRP3蛋白表达及IL-1β、IL-18升高程度明显降低（ P均＜0．05）。结论 NLRP3炎性体可促进小鼠脑IR损伤,主要通过增加细胞因子释放和促进神经元凋亡实现的。     

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...     

体内外高脂对肝脏NLRP3炎性小体相关基因表达的影响

背景:炎症-免疫系统活化是非酒精性脂肪性肝病(NAFLD)发生、发展的重要机制。炎性小体介导的促炎细胞因子活化在NAFLD中的作用日益受到重视。目的:探讨体内外高脂处理对肝脏NLRP3炎性小体相关基因表达的影响。方法:30只C57BL/6J小鼠随机分为高脂饮食组和正常饮食组(对照组),喂饲16周后处死小鼠,光学显微镜下观察肝组织病理学表现。以胶原酶原位灌注法分离正常饮食组小鼠肝细胞,分别以含饱和脂肪酸[棕榈酸(PA)]、单不饱和脂肪酸[油酸(OA)]、多不饱和脂肪酸[二十二碳六烯酸(DHA)]的培养液培养,以油红O染色检测肝细胞内脂质沉积。以real-time PCR法和蛋白质印迹法检测肝组织和肝细胞中的NLRP3、caspase-1、白细胞介素(IL)-1βmRNA和NLRF3蛋白表达。结果:高脂饮食组小鼠肝组织内可见空泡样脂肪变性。PA、OA和DHA组肝细胞内可见中-大量脂质沉积。与对照组相比,高脂饮食组小鼠肝组织内NLRF3、caspase-1、IL-1βmRNA表达显著升高(P0.05)。PA组肝细胞NLRP3和IL-IβmRNA表达显著高于对照组(P0.05),DHA组NLRP3和IL-1βmRNA表达显著低于对照组(P0.05),PA、OA、DHA组caspase-1 mRNA表达与对照组相比差异无统计学意义(P0.05)。PA、OA组NLRP3蛋白表达较脂多糖(LPS)组升高,DHA组NLRP3蛋白表达较LPS组降低。结论:肝内脂质尤其是饱和脂肪酸沉积可引起NLRP3炎性小体相关基因表达升高,促进肝脏局部炎症反应和NAFLD进展,而多不饱和脂肪酸可降低NLRP3炎性小体相关基因表达,可能具有抗炎、保护肝细胞的作用。     

NLRP3炎性小体在炎症性肠病中的研究进展

炎症性肠病（IBD）是一类因免疫反应失调所致的反复发作的肠道慢性炎症性疾病,包括克罗恩病（CD）和溃疡性结肠炎（UC）。白细胞介素（IL）-1β和IL-18是IBD发病中的重要致炎因子,近年研究发现NLRP3炎性小体可调节IL-lβ和IL-18的分泌,因此有望成为IBD治疗的新靶点。本文就NLRP3炎性小体在IBD中的研究进展作一综述．并提出未来的可能研究方向。     

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。     

Role of NLRP3 and NLRP1 inflammasomes signaling pathways in pathogenesis of rheumatoid arthritis

Objective:To investigate the role of NLRP3 and NLRP1 inflammasomes signaling pathways in rheumatoid arthritis(RA).Methods:A total of 36 patients with RA were selected,peripheral blood mononuclear cell(PBMC)and granulocyte were separated from venous blood.RT-qPCR method was used to detect the expression level and diversity of NLRP3 and NLRP1 in PBMC and granulocyte mRNA in patieuts with RA.and detect the mRNA expression of downstream factor IL-1β.The correlation between RA and the expression of NLRP3 aud NLRP1 was analyzed.Normal 30 cases were set as control group.Results:Expression levels of NLRP1.and caspase-1mRNA in PBMC of RA group were significautly lower than those of control group(P0.05).while there was no significant differeuee in expression levels of NLRP3,ASC.IL-1βmRNA between these two groups(P0.05);NLRP3,caspase-1,and ASC mRNA expression in granulocyte of RA patients were significantly lower than those in control group(P0.05).There was no currelation between rheumatoid factor and expression levels of NLRP3.ASC.caspase-1 mRNA in RA group(P0.05);NLRP1,IL-1βmRNA expression level had a negative corrlation with anti-rheunatoid factor antibody(P=0.0332,0.0340).Conclusions:NLRP3 and NLRP1 inflammasomes signaling pathways are involved in RA inflammatory reaction process as protective factors,and play an important role in RA inflammatory mechanisms.     

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。     

NLRP3炎性小体与心血管疾病

核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎性小体是由NLRP3、衔接蛋白凋亡相关斑点样蛋白(ASC)和效应蛋白胱天蛋白酶(caspase)-1组成的多蛋白复合体,广泛存在于人体的各种免疫细胞及非免疫细胞,参与体内炎性反应。研究表明,NLRP3炎性小体在心血管疾病的发生发展中发挥重要作用。NLRP3炎性小体及其活化产物的拮抗剂可用于心血管疾病的预防及治疗。该文介绍NLRP3炎性小体与心血管疾病的关系以及与NLRP3炎性小体相关的心血管疾病的治疗策略。     

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated speck-like protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.Proinflammatory cytokines of the interleukin-1 (IL-1) family are critical regulators of host responses to infection and orchestrate damaging inflammatory responses that occur during disease (1). One of the main mediators of damaging sterile inflammation is IL-1β, which is implicated in the etiology of many major diseases, including acute cerebrovascular disease (2). Acute cerebrovascular disease presents as a range of conditions, including devastating injuries such as subarachnoid hemorrhage (SAH) and ischemic stroke, which account for up to 10% of mortality worldwide and are the leading cause of morbidity (2). Treatments for acute stroke are limited to thrombolysis for up to 10% of all strokes, antiplatelet agents, and stroke unit care. Thus, treatment of acute cerebrovascular disease remains an area of unmet clinical need. Understanding the mechanisms regulating production of IL-1β during ischemic brain injury may lead to the identification of new therapeutic targets.IL-1β is produced by many cells, most commonly those of macrophage lineage, as a pro–IL-1β precursor. Pro–IL-1β is expressed in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) that bind to pattern recognition receptors (PRRs) to up-regulate proinflammatory gene expression (3, 4). PAMPs are motifs carried by pathogens, such as bacterial endotoxin (or LPS), and DAMPs are commonly endogenous molecules released by necrosis. Pro–IL-1β is inactive and remains intracellular until a further PAMP or DAMP stimulation activates cytosolic PRRs, often of the nucleotide-binding domain and leucine-rich repeat containing receptor (NLR) family, to form large multiprotein complexes called inflammasomes (5). These complexes consist of the PRR, procaspase-1, and, depending upon the PRR, an adaptor protein called ASC, that interact via CARD and pyrin homology-binding domains (5). When the PRR senses PAMPs or DAMPs, it recruits ASC, which in turn recruits caspase-1, causing its activation. Caspase-1 then processes pro–IL-1β to a mature form that is rapidly secreted from the cell (5). The activation of caspase-1 can also cause cell death (6).A number of inflammasome-forming PRRs have been identified, including NLR family, pyrin domain containing 1 (NLRP1); NLRP3; NLRP6; NLRP7; NLRP12; NLR family, CARD domain containing 4 (NLRC4); AIM 2 (absent in melanoma 2); IFI16; and RIG-I (5). Of these inflammasomes identified to date, the best characterized, and most strongly associated with sterile inflammation, is formed by NLRP3 (7). Indeed, there are now several studies suggesting that NLRP3 inflammasomes contribute to ischemic brain injury (8, 9). However, the picture is more complicated. NLRP1 inflammasomes have been implicated in several models of brain injury (6, 10, 11), as have AIM2 inflammasomes, which are suggested to mediate pyroptotic neuronal cell death (12). There is also evidence supporting a role for caspase-1 in brain injury (13), with a selective caspase-1 inhibitor, VRT-018858, a nonpeptide, active metabolite of the prodrug pralnacasan, showing marked protection in a rat model of stroke (14). However, data for the related caspase-1 inhibitor VRT-043198 suggest that it is also an effective inhibitor of caspase-4 (15), a human ortholog of caspase-11. Caspase-11 is also implicated in ischemic brain injury (16, 17), and given that we now also know that the original caspase-1^−/− mouse is also deficient in caspase-11 (18), it is clear that caspase-11 could have a role in ischemic brain injury. Our aim here was to elucidate which inflammasomes contribute to ischemic brain injury, using mice in which specific inflammasome components are deleted (^−/−).     

NLRP3炎症小体在肝脏疾病发病中的作用研究进展

炎症小体是一种存在于细胞浆中的多蛋白复合物,是机体固有免疫的重要组分之一。在核苷酸结合寡聚化结构域（NOD）样受体家族（NOD-like receptors,NLRs）中,NLRP3炎症小体主要是由NLRP3、凋亡相关的斑点样蛋白（ASC）和半胱氨酸的天冬氨酸蛋白水解酶（Caspase-1）等相互结合而形成的,具有调节免疫和抗微生物等作用。近年来发现其在多种肝脏疾病的发生、发展过程中发挥着巨大作用。本文主要介绍NLRP3炎症小体的激活通路、作用机制、表达调控及其与肝脏疾病发病的关系。     

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炎性小体与慢性炎症相关疾病的研究进展

炎性小体是先天免疫系统的重要组成部分,其中研究热点为NOD样受体蛋白3(NOD-like receptor protein 3,NLRP3)炎性小体,通过激活相应的信号途径参与多种慢性炎症疾病的发生发展。近年来,NLRP3炎性小体在动脉粥样硬化、非酒精性脂肪性肝病、阿尔茨海默病、慢性阻塞性肺疾病和慢性肾脏病等疾病的发生进程中,发挥着重要作用。该文就炎性小体与慢性炎症相关疾病的研究进展作一综述。     

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。