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.     

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。     

核苷酸结合寡聚化结构域样受体3炎性小体在风湿免疫性疾病中的研究进展

核苷酸结合寡聚化结构域样受体3（NLRP3）炎性小体是核苷结合域样受体家族成员之一,主要由单核-巨噬细胞和树突状细胞表达,在固有免疫中发挥重要作用,其激活产物IL-1β和IL-18可导致免疫细胞聚集并诱发后续的适应性免疫应答。近年来NLRP3炎性小体备受关注,目前已有大量研究表明其与多种风湿免疫性疾病的发病密切相关,本...     

NLRP3炎性小体在寄生虫感染性疾病中的研究进展

<正>NLRP3炎性小体是由胞浆模式识别受体参与组装的多蛋白复合体,可以被多种不同的外源性和内源性信号激活,从而诱导促炎因子IL-1β和IL-18的成熟、释放,引起一系列炎性反应。NLRP3炎性小体与多种疾病的发生、发展密切相关,包括病毒性肝炎、动脉粥样硬化和2型糖尿病等,同时NLRP3炎性小体也参与了多种寄生虫疾病的发生发展过程,包括利什曼原虫病、枯氏锥虫病、疟疾、刚地弓形虫病和血吸虫病等。在寄生虫     

颈动脉粥样硬化患者外周血单核细胞NLRP3炎性小体表达的研究

目的:检测重度颈动脉粥样硬化患者外周血单核细胞NLRP3炎性小体表达水平,探讨NLRP3炎性小体在颈动脉粥样硬化形成中的作用。方法:收集重度颈动脉粥样硬化行颈动脉内膜剥脱术(CEA)患者30例为观察组,无颈动脉粥样硬化形成的健康者20例为对照组。采静脉血20 ml,采用Reak-time PCR检测外周血单核细胞NLRP3炎性小体备组分、IL-1β、IL-18 mRNA表达,Western-blot法检测其蛋白表达,酶联免疫吸附试验(ELISA)检测血浆IL-1β和IL-18水平。应用多元线性逐步回归分析外周血单核细胞NLRP3炎性小体备组分、IL-1β、IL-18 mRNA及血浆IL-1β、IL-18的危险因素,并采用Pearson相关分析其与颈动脉mean-IMT、max-IMT的关系。结果:观察组外周血单核细胞NLRP3 mRNA(5.51±2.52)、Caspase-1 mRNA(3 467.84±1 057.99)、IL-1βmRNA(1 852.04±1 503.22)、IL-1βmRNA(5.67±3.15)表达量,血浆IL-1β(31 701.63±1 930.16)pg/L、IL-18(332.70±35.61)ng/L水平均显著高于对照组(均P0.001)。观察组外周血单核细胞ASC mRNA表达量(84.17±25.78)与对照组(73.54±10.30)差异无统计学意义。多元线性逐步回归分析显示,高血压、LDL-C、TG、UA是激活NLRP3炎性小体表达及血浆IL-1β、IL-18水平的重要危险因素。观察组颈部超声mean-IMT与外周血单核细胞NLRP3 mRNA(r=0.380,P=0.038)、Caspase-1 mRNA(r=0.381,P=0.038)、血浆IL-1β(r=0.432,P=0.017)、血浆IL-18(r=0.441,P=0.015)呈正相关。观察组颈部超声max-IMT与血浆IL-1β(r=0.419,P=0.021)、血浆IL-18(r=0.382,P=0.037)呈正相关。结论:重度颈动脉粥样硬化患者外周血单核细胞NLRP3炎性小体活化,并与颈动脉粥样硬化的严重程度相关,提示NLRP3炎性小体可能参与了颈动脉粥样硬化发生发展,LDL-C、TG、UA、高血压可能是激活NLRP3炎性小体表达的重要危险因素。     

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。     

TXNIP介导的NLRP3炎症小体激活在心肌微血管内皮细胞缺氧/复氧损伤中的作用

目的 研究硫氧还蛋白结合蛋白（TXNIP）介导的NLRP3炎症小体激活在心肌微血管内皮细胞（CMECs）缺氧/复氧（H/R）损伤中的作用。方法 分离培养C57BL/6J小鼠CMECs,随机分为对照组、H/R损伤组、H/R+Scrambled siRNA组和H/R+TXNIP siRNA组。各组处理后使用ELISA试剂盒检测细胞IL-1β水平,采用免疫共沉淀的方法检测TXNIP和NLRP3的相互作用,Western blot检测TXNIP和NLRP3的表达水平,乳酸脱氢酶试剂盒检测细胞培养上清LDH释放情况和细胞Caspase-3活性。结果 与对照组相比,H/R后CMECs的NLRP3表达水平明显升高（P<0.05）,NLRP3炎症小体激活（IL-1β水平升高,P<0.01）,且TXNIP和NLRP3的结合效果明显增强（P<0.01）。运用TXNIP siRNA抑制TXNIP表达后行H/R处理,与H/R+Scrambled siRNA组相比,NLRP3炎症小体激活水平明显下降（IL-1β水平降低）,细胞Caspase-3活力和LDH释放水平均显著降低（均P<0.05）。结论 在CMECs发生H/R损伤时,NLRP3炎症小体激活,TXNIP和NLRP3的相互作用增强;抑制TXNIP表达后,NLRP3炎症小体激活水平降低,内皮损伤减轻。说明TXNIP介导的NLRP3炎症小体激活参与CMECs的H/R损伤,可能成为CMECs的H/R损伤的新机制。     

炎症小体与糖尿病并发症

固有免疫是机体的第一道防线。其家族成员NLRP3炎症小体是炎性免疫反应的重要组成部分,它不仅是炎l生反应的“感受器”,亦是炎性反应的“调节器”。NLRP3炎症小体能够识别内源性危险信号,激活e,aspase-1,继而活化白细胞介素（IL）-1β、IL-18等细胞因子,激发炎性反应瀑布效应,在糖尿病及其并发症中起重要作用。高血糖、高血脂和高血尿酸可激活NLRP3炎症小体,活化的NLRP3炎症小体通过K＋通道模型、溶酶体破坏模型及活性氧簇模型介导糖尿病肾病、糖尿病视网膜病变和动脉粥样硬化的发生、发展。     

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。     

IL-33在炎症性肠病中的研究进展

白细胞介素-33（IL-33）是近年来发现的一种IL-1家族的细胞因子,其受体为ST2。IL-33具有双重作用,一方面在正常状态下作为细胞核内因子,结合核小体蛋白,发挥转录抑制作用。另一方面,在炎性反应刺激作用下,作为一种促炎细胞因子参与调节Th2型免疫应答,诱导前炎性细胞因子的表达。近期研究发现,IL-33在炎症性肠病（IBD）的发生发展中起着重要作用。此文就IL-33在IBD中作用的研究进展作一综述。     

Inflammatory bowel diseases and inflammasome

Inflammatory bowel disease (IBD), the most important entities being ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory conditions that result from chronic dysregulation of the mucosal immune system in the intestinal tract. Although the precise pathogenesis of IBD is still incompletely understood, increased levels of proinflammatory cytokines, including interleukin (IL)-1b, IL-18 and tumor necrosis factor-a, are detected in active IBD and correlate with the severity of inflammation, indicating that these cytokines may play a key role in the development of IBD. Recently, the intracellular nucleotide-binding oligomerization domain-like receptor (NLR) family members, including NLRP1, NLRP3, NLRC4 and NLRP6, are emerging as important regulators of intestinal homeostasis. Together, one of those aforementioned molecules or the DNA sensor absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein containing 'a caspase recruitment domain (CARD)' (ASC) and caspase-1 form a large (> 700 kDa) multi-protein complex called the inflammasome. Stimulation with specific microbial and endogenous molecules triggers inflammasome assembly and caspase-1 activation. Activated caspase-1 leads to the secretion of proinflammatory cytokines, including IL-1b and IL-18, and the promotion of pyroptosis, a form of phagocyte cell death induced by bacterial pathogens, in an inflamed tissue. Therefore, inflammasomes are assumed to mediate host defense against microbial pathogens and gut homeostasis, so that their dysregulation might contribute to IBD pathogenesis. This review focuses on recent advances of the role of NLRP3 inflammasome signaling in IBD pathogenesis. Improving knowledge of the inflammasome could provide insights into potential therapeutic targets for patients with IBD.     

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.     

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。     

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...     

Importance of NLRP3 Inflammasome in Abdominal Aortic Aneurysms

Abdominal aortic aneurysm (AAA) is a chronic inflammatory degenerative aortic disease, which particularly affects older people. Nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome is a multi-protein complex and mediates inflammatory responses by activating caspase 1 for processing premature interleukin (IL)-1β and IL-18. In this review, we first summarize the principle of NLRP3 inflammasome activation and the functionally distinct classes of small molecule NLRP3 inflammasome inhibitors. Next, we provide a comprehensive literature review on the expression of NLRP3 inflammasome effector mediators (IL-1β and IL-18) and components (caspase 1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and NLRP3) in clinical and experimental AAAs. Finally, we discuss the influence of genetic deficiency or pharmacological inhibition of individual effector mediators and components of NLRP3 inflammasome on experimental AAAs. Accumulating clinical and experimental evidence suggests that NLRP3 inflammasome may be a promise therapeutic target for developing pharmacological strategies for clinical AAA management.     

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...     

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。     

TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury

NLRP3 inflammasome is necessary for initiating acute sterile inflammation. Recent studies have demonstrated that NLRP3 inflammasome is up-regulated and mediates myocardial ischemia/reperfusion (MI/R) injury. However, the signaling pathways that lead to the activation of NLRP3 inflammasome by MI/R injury have not been fully elucidated. C57BL/6J mice were subjected to 30 min ischemia and 3 or 24 h reperfusion. The ischemic heart exhibited enhanced inflammasome activation as evidenced by increased NLRP3 expression and caspase-1 activity and increased IL-1β and IL-18 production. Intramyocardial NLRP3 siRNA injection or an intraperitoneal injection of BAY 11-7028, an inflammasome inhibitor, attenuated macrophage and neutrophil infiltration and decreased MI/R injury, as measured by cardiomyocyte apoptosis and infarct size. The ischemic heart also exhibited enhanced interaction between Txnip and NLRP3, which has been shown to be a mechanism for activating NLRP3. Intramyocardial Txnip siRNA injection also decreased infarct size and NLRP3 activation. In vitro experiments revealed that NLRP3 was expressed in cardiac microvascular endothelial cells (CMECs), but was hardly expressed in cardiomyocytes. Simulated ischemia/reperfusion (SI/R) stimulated NLRP3 inflammasome activation in CMECs, but not in cardiomyocytes. Moreover, CMECs subjected to SI/R injury increased interactions between Txnip and NLRP3. Txnip siRNA diminished NLRP3 inflammasome activation and SI/R-induced injury, as measured by LDH release and caspase-3 activity in CMECs. ROS scavenger dissociated TXNIP from NLRP3 and inhibited the activation of NLRP3 inflammasome in the CMECs. For the first time, we demonstrated that TXNIP-mediated NLRP3 inflammasome activation in CMECs was a novel mechanism of MI/R injury. Interventions that block Txnip/NLRP3 signaling to inhibit the activation of NLRP3 inflammasomes may be novel therapies for mitigating MI/R injury.     

Dietary saturated fatty acid and polyunsaturated fatty acid oppositely affect hepatic NOD-like receptor protein 3 inflammasome through regulating nuclear factor-kappa B activation

AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation.METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid(PUFA)-enriched diet. Primary hepatocytes were treated with either saturated fatty acids(SFAs) or PUFAs as well as combined with lipopolysaccharide(LPS). The expression of NOD-like receptor protein 3(NLRP3) inflammasome, peroxisome proliferator-activated receptor-γ and nuclear factor-kappa B(NF-κB) was determined by real-time PCR and Western blot. The activity of Caspase-1 and interleukine-1β production were measured.RESULTS: high-fat diet-induced hepatic steatosis was sufficient to induce and activate hepatic NLRP3 inflammasome. SFA palmitic acid(PA) directly activated NLRP3 inflammasome and increased sensitization to LPS-induced inflammasome activation in hepatocytes. In contrast, PUFA docosahexaenoic acid(Dh A) had thepotential to inhibit NLRP3 inflammasome expression in hepatocytes and partly abolished LPS-induced NLRP3 inflammasome activation. Furthermore, a highfat diet increased but PUFA-enriched diet decreased sensitization to LPS-induced hepatic NLRP3 inflammasome activation in vivo. Moreover, PA increased but Dh A decreased phosphorylated NF-κB p65 protein expression in hepatocytes.CONCLUSION:Hepatic NLRP 3 inflammasome activation played an important role in the development of non-alcoholic fatty liver disease. Dietary SFAs and PUFAs oppositely regulated the activity of NLRP3 inflammasome through direct activation or inhibition of NF-κB.     

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。