NLRP3炎性体在心肌病和心律失常中的作用及研究进展

NLRP3炎性体是先天免疫反应的参与者，通过相关激活信号来触发炎症。NLRP3炎性体在心肌细胞和心脏成纤维细胞中表达，通过水解含半胱氨酸的天冬氨酸蛋白水解酶(caspase-1)前体生成caspase-1促使白介素（IL）-1β、IL-18的成熟和释放而导致细胞焦亡，其浸润影响到心肌病和心律失常等心血管疾病的发生发展过程。在这篇综述中，我们介绍了NLRP3炎性体在心肌病和心律失常中的作用及相关机制，对探索针对NLRP3炎症体在此类疾病中的治疗方案有重要意义。     

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炎症小体在心力衰竭中的作用及相关治疗的研究进展

心力衰竭是许多心血管疾病的终末阶段,由于人口老龄化、心力衰竭合并症和危险因素负担加重,患病率不断增加。几十年来虽然在其诊疗方面有了巨大的进展,但目前仍缺乏具体且有效的治疗方案。NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体是一种蛋白质复合物,可参与心室重塑病理生理过程,进而影响心力衰竭的发生和进展。抑制NLRP3炎症小体激活是减少心力衰竭不良心室重塑和改善左心室功能的可行策略。现就NLRP3炎症小体的结构功能、激活途径、在心力衰竭中的作用及相关治疗进行综述。     

急性心肌梗死后心室重塑中的炎症反应

目前认为急性心肌梗死 (AMI)后心室重塑主要由于大面积透壁性心肌梗死 (MI)、心肌缺血、心室负荷过重和神经激素异常激活等因素所致。AMI后MI区经历了一个修复过程 ,炎症反应是创伤愈合和瘢痕形成的必要条件 ,MI区是否发生炎症反应 ?这种炎症是生理性反应 ,还是病理性反应 ?在动物实验中观察到MI后的心肌炎症反应。1 971年 ,Hill和Ward首次用大鼠MI模型证实缺血性心肌损伤能够激活补体的级联反应。Varda Bloom等在大鼠MI模型中找到淋巴细胞介导心肌细胞损害的证据。从MI大鼠获得的T细胞增殖指数明显高于假手术组和正常对照组。淋…     

线粒体相关的NLRP3炎性体激活

炎性体自发现以来,其在炎症反应中的作用就备受关注。NRLP3炎性体是目前研究最多的炎性体,其激活不仅启动免疫反应防御微生物感染,而且还参与包括急性肺损伤在内多种疾病的发生和发展。大量研究表明,线粒体代谢、线粒体自噬和凋亡、线粒体DNA释放等都与NRLP3炎性体的调节相关,可见线粒体在NLRP3炎性体的激活中发挥着重要作用。现就线粒体相关的NLRP3炎性体激活进行综述。     

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。     

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。     

糖尿病血管老化过程中调控NLRP3炎症小体活性的信号通路研究进展

糖尿病相关的代谢异常可导致糖尿病性血管老化,引发一系列血管并发症。糖尿病性血管老化与炎症反应密切相关,核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎性小体参与慢性无菌性炎症反应、氧化应激等进程,是糖尿病发展的重要环节。调控NLRP3炎症小体活性的信号通路可分为促进激活与抑制激活两类,核因子κB、活性氧簇（ROS）/硫氧还蛋白互作蛋白信号通路具有促进NLRP3炎症小体的转录、翻译与修饰以及促进ROS生成的作用,能够激活NLRP3炎症小体、诱导炎症反应与氧化应激,从而加速血管内皮细胞的老化;磷酸腺苷活化蛋白激酶、核因子红细胞系2相关因子2信号通路具有抑制NLRP3翻译与转录、阻断炎症小体组装与调节自噬等作用,对NLRP3炎症小体的激活进行负向调节,从而抑制炎症反应、氧化应激反应与细胞焦亡,可有效延缓血管老化。在糖尿病环境下,干预NLRP3炎症小体的启动、激活与分泌,可抑制糖尿病性血管老化的进展,是防治糖尿病慢性血管并发症的潜在靶点。     

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。     

脂联素抑制炎症小体NLRP3表达减轻高糖高脂诱导内皮细胞损伤

目的 研究脂联素（APN）是否通过抑制炎症小体NLRP3表达减轻高糖高脂所致的内皮细胞损伤。方法 将培养的人脐静脉内皮细胞（human umbilical vein endothelial cells,HUVECs）分为6组:对照组、高糖高脂组、对照+ NLRP3 siRNA组,高糖高脂组+NLRP3 siRNA组,对照+APN组,高糖高脂+APN组。培养48 h后检测细胞存活率、凋亡率、炎症小体NLRP3表达水平。结果 与对照组相比,高糖高脂组细胞存活率显著下降,细胞凋亡显著升高,炎症小体NLRP3表达水平显著升高（均P<0.05）;炎症小体NLRP3 siRNA可有效的抑制炎症小体NLRP3的表达,改善高糖高脂引起的内皮细胞损伤（均P<0.05）;APN能抑制高糖高脂引起的炎症小体NLRP3表达增多,进而减轻高糖高脂引起的内皮损伤（均P<0.05）。结论 炎症小体NLRP3表达增多是高糖高脂诱导人脐静脉内皮细胞凋亡的内在机制,而脂联素可以通过抑制炎症小体NLRP3的过度表达发挥内皮保护作用。伤,降低心肌炎症反应。     

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。     

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.     

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...     

炎性小体在脑缺血中的作用

固有免疫在脑缺血后炎性损伤中发挥重要作用,其中炎性小体被认为是一个关键因素.炎性小体是一种大分子蛋白质复合物,可识别各种病原体相关分子模式和损伤相关分子模式介导免疫炎性反应.研究显示,脑缺血或脑缺血再灌注可诱导NLRP1和NLRP3炎性小体激活.文章对炎性小体的结构、活化、调控以及在脑缺血中的作用进行了综述.     

Calcium-Sensing Receptor on Neutrophil Promotes Myocardial Apoptosis and Fibrosis After Acute Myocardial Infarction via NLRP3 Inflammasome Activation

BackgroundThe infiltration of neutrophils aggravates inflammatory response in acute myocardial infarction (AMI), and the role of calcium-sensing receptor (CaSR) in neutrophil-associated inflammation is largely unknown. The aim of this study was to evaluate the regulatory effects of CaSR on nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in neutrophils and to explore its role in AMI-related ventricular remodelling.MethodsThe expression of CaSR, NLRP3 inflammasome, and interleukin 1β (IL-1β) in peripheral blood and infiltrating neutrophils in patients and rats with AMI was detected by western blotting and immunofluorescence. Cardiomyocyte apoptosis was detected by western blotting and transmission electron microscopy. The degree of fibrosis was evaluated by Masson staining and western blotting.ResultsWe found upregulation of CaSR, NLRP3 inflammasome, Caspase-1, and IL-1β in peripheral neutrophils from patients with AMI compared with matched healthy controls, peaking on day 1 and decreasing gradually till 7 days. Peripheral and infiltrating neutrophils from rats with AMI showed the same trend. Calindol enhanced NLRP3 inflammasome activation and IL-1β release in neutrophils from healthy volunteers, which was blocked by inhibitors of the PLC-IP₃ pathway and ER-Ca²⁺ release. Calhex-231 decreased NLRP3 inflammasome activation and IL-1β release in neutrophils from patients with AMI. The calindol-stimulated neutrophils from healthy rats promoted cardiomyocyte apoptosis and fibrosis of cardiac fibroblasts from healthy rats, which were inhibited by calhex-231.ConclusionThe results suggest that CaSR activates NLRP3 inflammasome in neutrophils, contributing to ventricular remodelling after AMI. CaSR inhibition may be a potential therapeutic target for heart failure in AMI.     

Rosuvastatin Alleviates Diabetic Cardiomyopathy by Inhibiting NLRP3 Inflammasome and MAPK Pathways in a Type 2 Diabetes Rat Model

Purpose

Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is important in inflammation of several diabetic complications. However, the potential role of NLRP3 inflammasome in the inflammatory process of diabetic cardiomyopathy (DCM) remains unclear. Although rosuvastatin (RSV) has an anti-inflammatory effect on some cardiovascular diseases, its influence on DCM is incompletely understood. We aimed to explore the effect on and underlying mechanism of RSV in DCM, and whether NLRP3 is a target for RSV.

Methods

Type 2 diabetes was induced in rat. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. The expression of factors was determined by real-time RT-PCR and western blot. Eight-week RSV treatment and NLRP3 gene silencing were used to investigate the effect and underlying target of RSV in DCM.

Results

Compared with controls, diabetic rats showed severe metabolic disorder, cardiac dysfunction, fibrosis, disorganized ultrastructure, and excessive activation of thioredoxin interacting/inhibiting protein (TXNIP, p?<?0.05), NLRP3 inflammasome (NLRP3, p?<?0.01; apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC], p?<?0.05; caspase-1, p?<?0.01), interleukin-1β (p?<?0.01) and mitogen-activated protein kinases (MAPKs, all p?<?0.01). Compared with diabetes alone, RSV ameliorated the overexpression of NLRP3 inflammasome (NLRP3, p?<?0.05; ASC, p?<?0.05; pro-caspase-1 p?<?0.05, caspase-1 p20, p?<?0.01) and MAPKs (all p?<?0.05), which paralleled the cardiac protection of RSV. Silencing NLRP3 ameliorated cardiac remodeling and dysfunction. The beneficial effects of RSV in vehicle-treated rats were all abrogated in NLRP3-silenced rats.

Conclusions

The beneficial effect of RSV on DCM depended on inhibited NLRP3 inflammasome, and correlated with suppression of the MAPKs.     

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.