Morroniside alleviates coxsackievirus B3-induced myocardial damage apoptosis via restraining NLRP3 inflammasome activation

Coxsackievirus B3 (CVB3)-induced myocardial damage always leads to serious heart failure by inducing cardiac injury. NLRP3 inflammasome activation has been identified as a central player in the pathogenesis of CVB3-induced viral myocarditis. Therefore, restraining NLRP3 inflammasome activation has been supposed to significantly alleviate the severity of myocardial damage and improve cardiac function. Morroniside (MR), one of the main iridoid glycosides, has the ability to depress the production of reactive oxygen species (ROS) and restrain the expression of caspase-3 and -9. Of importance, ROS and caspase are essential for NLRP3 inflammasome activation in response to CVB3 infection. Therefore, in the present study, MR was selected as a model drug to alleviate CVB3-induced myocardial damage. The results of cardiac function index determination showed that abnormal indexes including mean arterial pressure, heart rate, and left ventricular systolic pressure of myocardial damage rats could be recovered by treating with MR. Such results can be further verified by histopathological evaluation, with the heart tissues of CVB3-infected rats displaying the most amount of H&E and TUNEL positive cells. The underlying mechanism by which MR improves the cardiac function was subsequently investigated. The detection of various gene levels indicated that NLRP3 inflammasome activation was inhibited by MR through down-regulating the expression of pro-inflammatory cytokines: interleukin (IL)-β and IL-18, the pivotal factors that lead to inflammatory responses. More importantly, the related genes, cardiac function indexes, and various myocardial damage markers of normal rats treated with MR did not exhibit any obvious changes compared with the control group, indicating a satisfactory biocompatibility of MR. In summary, MR holds a great potential in the alleviation of CVB3-induced myocardial damage with a negligible cytotoxicity to normal heart tissues.

Coxsackievirus B3 (CVB3)-induced myocardial damage always leads to serious heart failure by inducing cardiac injury.     

ASC deglutathionylation is a checkpoint for NLRP3 inflammasome activation

Activation of NLRP3 inflammasome is precisely controlled to avoid excessive activation. Although multiple molecules regulating NLRP3 inflammasome activation have been revealed, the checkpoints governing NLRP3 inflammasome activation remain elusive. Here, we show that activation of NLRP3 inflammasome is governed by GSTO1-promoted ASC deglutathionylation in macrophages. Glutathionylation of ASC inhibits ASC oligomerization and thus represses activation of NLRP3 inflammasome in macrophages, unless GSTO1 binds ASC and deglutathionylates ASC at ER, under control of mitochondrial ROS and triacylglyceride synthesis. In macrophages expressing ASC^C171A, a mutant ASC without glutathionylation site, activation of NLRP3 inflammasome is GSTO1 independent, ROS independent, and signal 2 less dependent. Moreover, Asc^C171A mice exhibit NLRP3-dependent hyperinflammation in vivo. Our results demonstrate that glutathionylation of ASC represses NLRP3 inflammasome activation, and GSTO1-promoted ASC deglutathionylation at ER, under metabolic control, is a checkpoint for activating NLRP3 inflammasome.     

Uropathogenic Escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation

Successful bacterial pathogens produce an array of virulence factors that allow subversion of the immune system and persistence within the host. For example, uropathogenic Escherichia coli strains, such as CFT073, express Toll/IL-1 receptor–containing (TIR-containing) protein C (TcpC), which impairs TLR signaling, thereby suppressing innate immunity in the urinary tract and enhancing persistence in the kidneys. Here, we have reported that TcpC also reduces secretion of IL-1β by directly interacting with the NACHT leucin-rich repeat PYD protein 3 (NLRP3) inflammasome, which is crucial for recognition of pathogens within the cytosol. At a low MOI, IL-1β secretion was minimal in CFT073-infected macrophages; however, IL-1β release was markedly increased in macrophages infected with CFT073 lacking tcpC. Induction of IL-1β secretion by CFT073 and tcpC–deficient CFT073 required the NLRP3 inflammasome. TcpC attenuated activation of the NLRP3 inflammasome by binding both NLRP3 and caspase-1 and thereby preventing processing and activation of caspase-1. Moreover, in a murine urinary tract infection model, CFT073 infection rapidly induced expression of the NLRP3 inflammasome in the bladder mucosa; however, the presence of TcpC in WT CFT073 reduced IL-1β levels in the urine of infected mice. Together, these findings illustrate how uropathogenic E. coli use the multifunctional virulence factor TcpC to attenuate innate immune responses in the urinary tract.     

Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects

BACKGROUND. Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome–linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity.METHODS. We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation.RESULTS. In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting.CONCLUSIONS. Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease.TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02122575","term_id":"NCT02122575"}}NCT02122575 and {"type":"clinical-trial","attrs":{"text":"NCT00442195","term_id":"NCT00442195"}}NCT00442195.FUNDING. Division of Intramural Research, NHLBI of the NIH.     

NLRP1和NLRP3炎性体的研究进展

炎性体作为一种新近发现的蛋白质复合物,其活化后可促进炎性因子的成熟与释放,在先天性免疫中发挥着重要的作用。本文就核苷酸结合寡聚化结构域样受体蛋白1（NLRP1）和3（NLRP3）炎性体的构成、激活机制及信号传导通路和相关的疾病做出综述,并对NLRP1和NLRP3炎性体与早产的关系做出推测。     

TNF-α和CRT双信号对RA患者滑膜组织NLRP3炎症小体的活化作用

目的研究肿瘤坏死因子-α(TNF-α)和钙网织蛋白(CRT)双信号对类风湿性关节炎(RA)患者成纤维样滑膜细胞(FLS)中核苷酸结合寡聚化结构域受体3(NLRP3)炎症小体活化的影响。方法采用间接免疫荧光染色法检测12例RA和10例骨性关节炎(OA)患者滑膜组织NLRP3、衔接蛋白凋亡相关斑点样蛋白(ASC)的表达,并与滑膜衬里层和衬里下层FLS标志物进行共定位研究。采用胶原酶消化法分离RA患者滑膜组织中FLS并进行体外培养。分别用不同浓度的TNF-α或脂多糖(LPS)(刺激剂)处理细胞,采用免疫印迹法和实时荧光定量聚合酶链反应(qRT-PCR)检测细胞NLRP3、白细胞介素1β前体(pro-IL-1β)和白细胞介素18前体(pro-IL-18)的蛋白和mRNA表达。加入尼日利亚菌素(Nigericin)或CRT后采用免疫印迹法检测FLS中半胱氨酸天冬氨酸特异性蛋白酶1(Caspase-1)活化片段p20的表达;收集细胞培养上清液,采用酶联免疫吸附试验(ELISA)检测分泌型白细胞介素(IL)-1β和IL-18水平。结果 RA患者滑膜组织中NLRP3炎症小体的主要成分NLRP3和ASC的平均荧光强度高于OA患者(P<0.01)。NLRP3、ASC和IL-1β裂解片段(cleaved IL-1β)与RA患者滑膜衬里层FLS表面标志物PDPN和衬里下层FLS表面标志物CD248均有共定位。体外细胞实验结果显示TNF-α可以促进FLS中NLRP3和pro-IL-1β的蛋白表达;与对照组(无刺激剂)相比,二者的mRNA表达显著增加(P<0.05、P<0.001),而LPS对RA患者FLS中NLRP3炎症小体的预活化无影响。TNF-α/Nigericin或TNF-α/CRT双信号能够促进FLS中Caspase-1的活化,导致Caspase-1活化片段p20呈浓度依赖性升高;与对照组相比,TNF-α/CRT组分泌型IL-1β显著升高(P<0.05)。结论 TNF-α/CRT双信号可促进RA患者FLS中NLRP3炎症小体的活化。     

MicroRNA-10 negatively regulates inflammation in diabetic kidney via targeting activation of the NLRP3 inflammasome

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Oxidative metabolism enables Salmonella evasion of the NLRP3 inflammasome

Microbial infection triggers assembly of inflammasome complexes that promote caspase-1–dependent antimicrobial responses. Inflammasome assembly is mediated by members of the nucleotide binding domain leucine-rich repeat (NLR) protein family that respond to cytosolic bacterial products or disruption of cellular processes. Flagellin injected into host cells by invading Salmonella induces inflammasome activation through NLRC4, whereas NLRP3 is required for inflammasome activation in response to multiple stimuli, including microbial infection, tissue damage, and metabolic dysregulation, through mechanisms that remain poorly understood. During systemic infection, Salmonella avoids NLRC4 inflammasome activation by down-regulating flagellin expression. Macrophages exhibit delayed NLRP3 inflammasome activation after Salmonella infection, suggesting that Salmonella may evade or prevent the rapid activation of the NLRP3 inflammasome. We therefore screened a Salmonella Typhimurium transposon library to identify bacterial factors that limit NLRP3 inflammasome activation. Surprisingly, absence of the Salmonella TCA enzyme aconitase induced rapid NLRP3 inflammasome activation. This inflammasome activation correlated with elevated levels of bacterial citrate, and required mitochondrial reactive oxygen species and bacterial citrate synthase. Importantly, Salmonella lacking aconitase displayed NLRP3- and caspase-1/11–dependent attenuation of virulence, and induced elevated serum IL-18 in wild-type mice. Together, our data link Salmonella genes controlling oxidative metabolism to inflammasome activation and suggest that NLRP3 inflammasome evasion promotes systemic Salmonella virulence.Pattern recognition receptors (PRRs) that detect and respond to evolutionarily conserved microbial structures such as LPS or peptidoglycan, as well as pathogen-specific virulence activities, are critical for host immune defense (Medzhitov, 2007; Vance et al., 2009). To promote infection, microbial pathogens inject virulence factors into the cytosol of infected cells to disrupt or modulate critical host physiological processes (Cornelis, 2006). During this process, contamination of the target cell cytosol by microbial components triggers cytosolic PRRs of the nucleotide binding domain leucine-rich repeat (NLR) family (Lamkanfi and Dixit, 2009). Diverse NLRs respond to a variety of endogenous and exogenous signals associated with infection, tissue stress, or damage. For example, NLRC4 responds to microbial products such as bacterial flagellin or structurally related specialized secretion system components that are injected into the cytosol of infected cells during infection by bacterial pathogens including Pseudomonas, Legionella, and Salmonella spp. (Miao et al., 2006; Molofsky et al., 2006; Sutterwala et al., 2007). NLRs recruit pro–caspase-1 to multiprotein complexes termed inflammasomes, where pro–caspase-1 is processed and activated, leading to cleavage and secretion of caspase-1–dependent cytokines (Martinon et al., 2002, 2007), as well as pyroptosis, a caspase-1–dependent pro-inflammatory cell death (Bergsbaken et al., 2009).Inflammasome activation and subsequent production of caspase-1–dependent cytokines is important for both innate and adaptive antimicrobial responses (Mariathasan and Monack, 2007), as IL-1 family cytokines released upon inflammasome activation promote neutrophil migration to infected tissues and drive T_H17 and T_H1 responses against mucosal pathogens (Chung et al., 2009; Ichinohe et al., 2009). How pathogens evade inflammasome activation, and whether persistent bacterial pathogens evade or suppress inflammasome activation to establish or maintain persistence remains poorly understood.Salmonella enterica species cause a range of disease from severe gastroenteritis to persistent systemic infection (Bäumler et al., 1998). Salmonella enterica serovar Typhimurium (Stm) invades host cells by means of a type III secretion system (T3SS) encoded on Salmonella pathogenicity island I (SPI-1; Lee, 1996; Collazo and Galán, 1997). Salmonella subsequently replicates within a Salmonella-containing vacuole (SCV) that is established and maintained by the activity of a second T3SS, encoded on a second pathogenicity island, SPI-2 (Cirillo et al., 1998; Hensel et al., 1998). Intestinal inflammation during Stm infection is triggered by NLRC4-dependent responses to Stm flagellin, accompanied by caspase-1–dependent cytokine secretion and pyroptosis (Franchi et al., 2012). Activity of a SPI-1 effector protein, SopE, also contributes to SPI-1–dependent inflammasome activation in intestinal epithelial cells (Müller et al., 2009). Within the inflamed intestine, specialized adaptations allow Stm to resist mucosal antimicrobial defenses (Raffatellu et al., 2009; Winter et al., 2010; Thiennimitr et al., 2011). However, flagellin expression is down-regulated at systemic sites (Cummings et al., 2005, 2006), and enforced flagellin expression enhances NLRC4 activation and bacterial clearance, indicating that inflammasome activation in response to bacterial flagellin is detrimental for Stm replication during systemic infection (Miao et al., 2010a; Stewart et al., 2011).NLRP3 responds to a wide variety of structurally unrelated molecules and activities, including extracellular ATP, bacterial pore-forming proteins, bacterial nucleic acids, crystals, and unsaturated fatty acids (Kanneganti et al., 2006; Mariathasan et al., 2006; Martinon et al., 2006; Hornung et al., 2008; Wen et al., 2011). While ATP, crystals, and the Yersinia T3SS all induce rapid formation of an NLRP3 inflammasome that leads to caspase-1 activation within 1–2 h (Mariathasan et al., 2006; Martinon et al., 2006; Brodsky et al., 2010), Stm induces delayed activation of a noncanonical NLRP3 inflammasome 12–16 h after infection (Broz et al., 2010). This noncanonical NLRP3 inflammasome is independent of the activities of the SPI-1 T3SS and instead is regulated by caspase-11 and TLR4-dependent production of type I interferon (Broz et al., 2012; Gurung et al., 2012; Rathinam et al., 2012). We therefore hypothesized that Stm might evade or prevent rapid activation of a canonical NLRP3 inflammasome, and that this evasion might contribute to systemic bacterial virulence. Several bacterial and viral pathogens evade NLRP3 inflammasome activation (Taxman et al., 2010; Gregory et al., 2011), but whether Salmonella is capable of doing so is unknown.To identify potential negative regulators of NLRP3 inflammasome activation, we generated and screened a transposon library of flagellin-deficient Stm mutants for elevated inflammasome activation in NLRC4-deficient BM-derived macrophages (BMDMs). Sequencing of candidate hits identified acnB, the gene encoding the TCA cycle enzyme aconitase, which converts citrate to isocitrate, as well as several other genes that had been previously isolated in a screen for Salmonella genes that are required for persistent Salmonella infection in vivo (Lawley et al., 2006). Intriguingly, isocitrate lyase (encoded by aceA), which generates glyoxylate from isocitrate in the glyoxylate cycle, contributes to persistent but not acute infection by Salmonella as well as Mycobacterium tuberculosis (McKinney et al., 2000; Fang et al., 2005).To test the potential role of Salmonella TCA cycle metabolism in inflammasome modulation, we generated targeted deletions in acnB as well as genes encoding other TCA cycle enzymes. Notably, deletion of aconitase, isocitrate lyase, or isocitrate dehydrogenase (icdA), but not other TCA enzymes, induced rapid NLRP3-dependent inflammasome activation in Stm-infected macrophages, suggesting that activity of these enzymes limits NLRP3 inflammasome activation by intracellular Salmonella. Moreover, aconitase-deficient Salmonella exhibited a defect in acute systemic virulence after oral administration and were deficient in their ability to persist in a chronic infection. These findings define the first genes that mediate NLRP3 inflammasome evasion by Salmonella and suggest that inflammasome evasion contributes to persistence of bacterial pathogens. Our data further suggest that sensing of bacterial metabolites may provide an additional level of innate immune recognition, and that regulation of metabolite production by intracellular pathogens represents a pathogen immune evasion strategy.     

BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity

Activity of the NLRP3 inflammasome, a critical mediator of inflammation, is controlled by accessory proteins, posttranslational modifications, cellular localization, and oligomerization. How these factors relate is unclear. We show that a well-established drug target, Bruton’s tyrosine kinase (BTK), affects several levels of NLRP3 regulation. BTK directly interacts with NLRP3 in immune cells and phosphorylates four conserved tyrosine residues upon inflammasome activation, in vitro and in vivo. Furthermore, BTK promotes NLRP3 relocalization, oligomerization, ASC polymerization, and full inflammasome assembly, probably by charge neutralization, upon modification of a polybasic linker known to direct NLRP3 Golgi association and inflammasome nucleation. As NLRP3 tyrosine modification by BTK also positively regulates IL-1β release, we propose BTK as a multifunctional positive regulator of NLRP3 regulation and BTK phosphorylation of NLRP3 as a novel and therapeutically tractable step in the control of inflammation.     

NLRP3炎性复合体及其在移植物抗宿主病中的作用

核苷酸结合寡聚化结构域样受体(NLR)家族含热蛋白结构域蛋白(NLRP)3炎性复合体为大分子蛋白复合物,通过半胱氨酸天冬氨酸蛋白酶(caspase)-1调控细胞因子白细胞介素(IL)-1β、-18成熟与分泌,诱导caspase-1依赖性细胞死亡(pyroptosis),其激活过程受到严密调控.近年来,多项研究结果显示NLRP3炎性复合体与移植物抗宿主病(GVHD)的发生、发展及其严重程度密切相关.笔者拟就NLRP3炎性复合体及其在GVHD防治中的作用进行综述.     

Resveratrol ameliorates LPS-induced acute lung injury via NLRP3 inflammasome modulation

NLRP3 inflammasome plays a pivotal role in the development of acute lung injury (ALI), accelerating IL-1β and IL-18 release and inducing lung inflammation. Resveratrol, a natural phytoalexin, has anti-inflammatory properties via inhibition of oxidation, leukocyte priming, and production of inflammatory mediators. In this study, we aimed to investigate the effect of resveratrol on NLRP3 inflammasome in lipopolysaccharide-induced ALI. Mice were intratracheally instilled with 3 mg/kg lipopolysaccharide (LPS) to induce ALI. Resveratrol treatment alleviated the LPS-induced lung pathological damage, lung edema and neutrophil infiltration. In addition, resveratrol reversed the LPS-mediated elevation of IL-1β and IL-18 level in the BAL fluids. In lung tissue, resveratrol also inhibited the LPS-induced NLRP3, ASC, caspase-1 mRNA and protein expression, and NLRP3 inflammasome activation. Moreover, resveratrol administration not only suppressed the NF-κB p65 nuclear translocation, NF-κB activity and ROS production in the LPS-treated mice, but also inhibited the LPS-induced thioredoxin-interacting protein (TXNIP) protein expression and interaction of TXNIP-NLRP3 in lung tissue. Meanwhile, resveratrol obviously induced SIRT1 mRNA and protein expression in the LPS-challenged mice. Taken together, our study suggests that resveratrol protects against LPS-induced lung injury by NLRP3 inflammasome inhibition. These findings further suggest that resveratrol may be of great value in the treatment of ALI and a potential and an effective pharmacological agent for inflammasome-relevant diseases.     

NLRP3炎性小体与2型糖尿病及冠心病并发症的关系

NLRP3炎性小体是炎性免疫反应的重要组成部分,它能够识别内源性危险信号,激活caspase-1,继而活化白细胞介素IL-1β和IL-18等细胞因子,参与诸多慢性疾病体内非感染性炎性反应。本文拟对NLRP3炎性小体与慢性炎性疾病2型糖尿病及冠心病并发症的关系作一综述。     

肌萎缩侧索硬化蛋白激活小胶质细胞NLRP3炎性体

小胶质细胞NLRP3炎症小体激活正在成为神经退行性变期间神经炎症的关键因素。β-淀粉样蛋白和α-突触核蛋白等致病蛋白的聚集体可触发小胶质细胞NLRP3激活,并导致半胱氨酸天冬氨酸酶激活和白介素-1β分泌。半胱氨酸天冬氨酸酶和白介素-1β均促进肌萎缩侧索硬化(ALS)小鼠SOD1G93A模型的疾病进展,这提示小胶质细胞NLRP3在该进程中起作用。然而,先前的研究表明SOD1G93A模型小鼠的小胶质细胞并不表达NLRP3,并且SOD1G93A蛋白在小胶质细胞中产生白介素-1β不依赖于NLRP3。本研究展示了使用Nlrp3-GFP基因敲入小鼠,在SOD1G93A小鼠中小胶质细胞表达NLRP3。结果表明,聚集和可溶性SOD1G93A均以剂量和时间依赖性方式激活小鼠原代小胶质细胞中的炎性体,导致半胱氨酸天冬氨酸酶和白介素-1β裂解、ASC斑点形成和白介素-1β分泌。重要的是,SOD1G93A不能诱导缺乏Nlrp3的小胶质细胞或用特异性NLRP3抑制剂MCC950预处理的小胶质细胞分泌白介素-1β,这证实NLRP3是介导SOD1诱导的小胶质细胞白介素-1β分泌的关键炎性体复合物。在TDP-43Q331K ALS小鼠模型中也观察到小胶质细胞NLRP3上调,并且TDP-43野生型和突变蛋白也能以NLRP3依赖性方式激活小胶质细胞炎症小体。从机制上,本研究确定活性氧簇和ATP的产生是SOD1G93A介导的NLRP3激活所需的关键事件。总之,本研究的数据表明ALS小胶质细胞表达NLRP3,病理性ALS蛋白激活了小胶质细胞NLRP3炎性体。因此,抑制NLRP3可能是阻止小胶质细胞神经炎症和ALS疾病进展的潜在治疗方法。     

The role of the NLRP3 inflammasome in the pathogenesis of airway disease

The incidences of respiratory diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD) are increasing dramatically. Significantly, there are currently no treatments that can slow or prevent the relentless progression of COPD; and a sub-population of asthmatics are resistant to available therapies. What is more, currently prescribed medication has only minimal effect on the symptoms suffered in these patient groups. There is therefore an urgent need to develop effective drugs to treat these diseases. Whilst asthma and COPD are thought to be distinct diseases, it is currently believed that the pathogenesis of both is driven by the chronic inflammation present in the airways of these patients. It is thus hypothesised that if the inflammation could be attenuated, disease development would be slowed and symptoms reduced. It is therefore paramount to determine the pathways driving/propagating the inflammation. Recently there has been a growing body of evidence to suggest that the multimeric protein complex known as the Inflammasome may play key roles in the inflammation observed in respiratory diseases. The aim of this review is to discuss the role of the NLRP3 Inflammasome, and its associated inflammatory mediators (IL-1β and IL-18), in the pathogenesis of asthma and COPD.     

NLRP3炎症小体作为肾脏疾病潜在治疗靶标的研究进展

急性肾损伤(acute kidney injury,AKI)和慢性肾脏病(chronic kidney disease, CKD)是肾脏常见病理状态。最近,大量证据表明肾脏疾病与炎症小体之间存在关联,尤其是核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain, NOD)样受体家族含pyrin结构域蛋白3(NOD-like receptor family pyrin domain-containing protein 3,NLRP3)炎症小体。 经典的NLRP3炎症小体是由NOD样受体(NOD-like receptors, NLRs)、凋亡相关的斑点样蛋白(apoptosis-associated speck-like protein containing a CARD, ASC)和半胱氨酸天冬氨酸蛋白酶1 (Caspase-1)组成的多蛋白复合物。大量的研究探索了NLRP3炎症小体在肾脏疾病发生发展中的机制以及在肾脏疾病中针对NLRP3炎症小体的治疗。本文综述了近几年NLRP3炎症小体在肾脏疾病中的作用的最新发现以及以NLRP3炎症小体为靶标的最新治疗策略。     

n-3 fatty acids, γ-linolenic acid,and antioxidants in sepsis

The usefulness of n-3 fatty acids, γ-linolenic acid and antioxidants in the critically ill is controversial. I propose that adverse outcome in the critically ill is due to excess production of proinflammatory cytokines and eicosanoids from polyunsaturated fatty acids (PUFAs), while generation of anti-inflammatory products of PUFAs may lead to a favorable outcome. Hence, I suggest that measurement of plasma levels of various cytokines, free radicals, and proinflammatory and anti-inflammatory products of PUFAs and correlating them to the clinical picture may pave the way to identify prognostic markers and develop newer therapeutic strategies to prevent and manage critical illness.     

Atorvastatin suppresses NLRP3 inflammasome activation via TLR4/MyD88/NF-κB signaling in PMA-stimulated THP-1 monocytes

AimsIncreasing evidence shows that NLRP3 inflammasome is closely associated with the progression of atherosclerosis. The purpose of the present study was to evaluate the effects of atorvastatin on NLRP3 inflammasome in PMA-stimulated THP-1 cells and explore its underlying mechanism.MethodsHuman monocytic THP-1 cells were pretreated with atorvastatin for 1 h and then induced by PMA for 48 h. Total protein was collected for real-time PCR and Western blot analysis. Cytokine IL-1β release was detected by ELISA assay. And the NF-κB p65 translocation was detected by cellular NF-κB translocation kit.ResultsIt was shown that atorvastatin significantly reduced the expression of NLRP3, the cleavage of caspase-1 and IL-1β in PMA-induced THP-1 cells. Moreover, Bay (a NF-κB inhibitor) treatment greatly suppressed the expression of NLRP3, the cleavage of caspase-1 and IL-1β in PMA-induced THP-1 cells, suggesting that the activation of NF-κB pathway takes part in regulating the expression of NLRP3 inflammasome. In addition, atorvastatin markedly inhibited the up-regulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and the activation of nuclear factor kappa b (NF-κB) in PMA-stimulated THP-1 cells.ConclusionsAtorvastatin exerts an anti-inflammatory effect by inhibiting NLRP3 inflammasome through suppressing TLR4/MyD88/NF-κB pathway in PMA-induced THP-1 monocytes.