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。     

NLRP3炎性小体在动脉型肺动脉高压中的研究进展

动脉型肺动脉高压(PAH)是一种以肺血管重构为主要病理特征的致死性疾病.肺血管重构与炎症密切相关,其中NLRP3炎性小体作为重要的炎症调节因子,在接收到外源性和内源性信号后,可促进促炎性因子的产生.众多研究表明,特异性或非特异性干预NLRP3炎性小体激活可抑制PAH病程的进展,NLRP3炎性小体似乎是PAH潜在的治疗靶...     

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炎性小体与急性呼吸窘迫综合征关系的研究进展

急性呼吸窘迫综合征(ARDS)是临床常见的危重症,NLRP3炎性小体是固有免疫反应的重要组成成分,参与炎性反应的过程.该文就NLRP3炎性小体在ARDS发生发展中的作用作一综述.     

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。     

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。     

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。     

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。     

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 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.     

Bacillus anthracis induces NLRP3 inflammasome activation and caspase-8–mediated apoptosis of macrophages to promote lethal anthrax

Lethal toxin (LeTx)-mediated killing of myeloid cells is essential for Bacillus anthracis, the causative agent of anthrax, to establish systemic infection and induce lethal anthrax. The “LeTx-sensitive” NLRP1b inflammasome of BALB/c and 129S macrophages swiftly responds to LeTx intoxication with pyroptosis and secretion of interleukin (IL)-1β. However, human NLRP1 is nonresponsive to LeTx, prompting us to investigate B. anthracis host–pathogen interactions in C57BL/6J (B6) macrophages and mice that also lack a LeTx-sensitive Nlrp1b allele. Unexpectedly, we found that LeTx intoxication and live B. anthracis infection of B6 macrophages elicited robust secretion of IL-1β, which critically relied on the NLRP3 inflammasome. TNF signaling through both TNF receptor 1 (TNF-R1) and TNF-R2 were required for B. anthracis-induced NLRP3 inflammasome activation, which was further controlled by RIPK1 kinase activity and LeTx-mediated proteolytic inactivation of MAP kinase signaling. In addition to activating the NLRP3 inflammasome, LeTx-induced MAPKK inactivation and TNF production sensitized B. anthracis-infected macrophages to robust RIPK1- and caspase-8–dependent apoptosis. In agreement, purified LeTx triggered RIPK1 kinase activity- and caspase-8–dependent apoptosis only in macrophages primed with TNF or following engagement of TRIF-dependent Toll-like receptors. Consistently, genetic and pharmacological inhibition of RIPK1 inhibited NLRP3 inflammasome activation and apoptosis of LeTx-intoxicated and B. anthracis-infected macrophages. Caspase-8/RIPK3-deficient mice were significantly protected from B. anthracis-induced lethality, demonstrating the in vivo pathophysiological relevance of this cytotoxic mechanism. Collectively, these results establish TNF- and RIPK1 kinase activity–dependent NLRP3 inflammasome activation and macrophage apoptosis as key host–pathogen mechanisms in lethal anthrax.

The bacterial pathogen Bacillus anthracis is a rare, but notoriously deadly pathogen in humans with mortality rates from anthrax varying from ∼20% for cutaneous anthrax to 80% and higher for inhalation anthrax. This encapsulated, spore-forming, gram-positive bacterial pathogen efficiently kills infected hosts through the systemic action of two secreted toxins (1). Edema toxin (EdTx) and lethal toxin (LeTx) share a receptor-binding protein named protective antigen (PA) that transfers the edema factor (EF) and lethal factor (LF) moieties into the cytosol of target cells, where the latter exert their cytopathic and cytotoxic effects (1, 2).Studies in macaques and mice identified LeTx as a major virulence factor driving systemic dispersion of vegetative bacteria, which ultimately may result in fatal anthrax (3, 4). LeTx internalization by macrophages drives macrophage cell death, which is a key early pathogenic event during spore infections that allows vegetative bacteria to establish systemic infection of its host (5). LF is a highly selective Zn²⁺-dependent metalloprotease that, once internalized, cleaves a subset of mitogen-activated protein kinase kinases (MAPKKs) to abolish downstream MAPK signaling in LeTx-intoxicated macrophages (6). In addition, macrophages of BALB/c and 129S mice express a LeTx-sensitive Nlrp1b allele that responds to LF-mediated cleavage with NLRP1b inflammasome activation and pyroptosis (7–9). However, human NLRP1 and the Nlrp1b allele of C57BL/6J (B6) macrophages are nonresponsive to LeTx, suggesting that B. anthracis may induce macrophage cell death through alternative mechanisms that are poorly understood.Here, we show that B. anthracis infection induces NLRP3 inflammasome activation and caspase-8–mediated apoptosis of B6 macrophages. Notably, B. anthracis sensitizes macrophages by promoting TNF production concomitantly with LeTx-mediated inactivation of p38 MAPK signaling. LeTx intoxication of TLR3/4- or TNF-activated macrophages similarly sensitized macrophages to TNF- and RIPK1 kinase activity–dependent NLRP3 inflammasome activation and cell death induction. Caspase-8/RIPK3-deficient mice were significantly protected from B. anthracis-induced lethality, demonstrating the in vivo pathophysiological relevance of this cytotoxic mechanism in lethal anthrax.     

NLRP3 Inflammasome Activation by Viroporins of Animal Viruses

Viroporins are a group of low-molecular-weight proteins containing about 50–120 amino acid residues, which are encoded by animal viruses. Viroporins are involved in several stages of the viral life cycle, including viral gene replication and assembly, as well as viral particle entry and release. Viroporins also play an important role in the regulation of antiviral innate immune responses, especially in inflammasome formation and activation, to ensure the completion of the viral life cycle. By reviewing the research progress made in recent years on the regulation of the NLRP3 inflammasome by viroporins of animal viruses, we aim to understand the importance of viroporins in viral infection and to provide a reference for further research and development of novel antiviral drugs.     

利拉鲁肽对糖尿病肾病大鼠NLRP3表达的影响

目的 探讨利拉鲁肽是否通过抑制NLRP3炎症小体（The NLRP3 inflammasome,NLRP3）的活化在糖尿病肾病（Diabetic Nephropathy,DKD）中发挥肾脏保护作用。方法 Wistar品系大鼠22只,雄性,4周龄,采用单纯随机抽样方法分为正常对照组（NC组,n=6）、利拉鲁肽干预DKD组（LIR组,n=8）和生理盐水干预DKD组（NS组,n=8）。LIR组予利拉鲁肽200μg•kg-1•d-1皮下注射,NS组予等体积的生理盐水皮下注射,NC组不做任何处理,共治疗4周。治疗结束后检测大鼠体重、24h尿总蛋白定量（Urinary total protein,UTP）、空腹血糖（Fasting blood-glucose,FPG）、甘油三酯（Transformational Grammar,TG）、胆固醇(Temperature Coefficient,TC)、血尿素氮（Blood Urea Nitrogen,BUN）、血肌酐（Silicon ControlledRectifier,Scr）等生化指标,各组大鼠肾组织苏木素-伊红染色(HE),光镜下观察肾组织病理形态学改变,Western-blot检测肾组织中NLRP3炎症小体蛋白表达,Elisa检测血清白介素-18（Interleukin - 18,IL-18）及血清白介素-1β（IL-1β）的水平。结果 利拉鲁肽组大鼠FBG、UTP、BUN、Scr、TC、TG等生化指标水平较生理盐水组改善;肾脏组织病理切片提示正常对照组肾小球、肾小管结构正常,生理盐水组可见肾小球体积增大、 结构紊乱,系膜外基质增多,基底膜增厚明显,利拉鲁肽组大鼠肾脏病理变化减轻;Western-blot检测提示经过利拉鲁肽的干预,NLRP3炎症小体的蛋白表达明显低于生理盐水组;Elisa检测提示生理盐水组IL-18、IL-1β水平明显增加,经利拉鲁肽干预后,IL-18、IL-1β水平下降。结论 利拉鲁肽可以改变糖尿病肾病大鼠的疾病进程,这可能与利拉鲁肽抑制NLRP3炎症小体的激活有关。     

NLRP3炎症小体在动脉粥样硬化中的作用机制和靶向炎症治疗的研究进展

动脉粥样硬化(As)是由一系列复杂因素引起的病理过程,包括内皮功能障碍、动脉血管壁中脂质沉积、巨噬细胞浸润、平滑肌细胞功能失调、泡沫细胞形成等,炎症反应在这一过程中发挥了重要的作用。NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体是炎症细胞的传导器,其激活后介导炎症反应,激活下游的白细胞介素18、白细胞介素1β,从而参与As的发生和发展。因此,针对NLRP3炎症小体和下游炎症因子的特异性抑制剂是目前临床药物研究的潜在靶点,有望成为治疗As的一种新的治疗措施。文章对NLRP3炎症小体的结构和激活机制及与As的关系进行了讨论,同时对靶向NLRP3炎症小体和下游炎症因子的药物进行了介绍。     

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。