细胞焦亡在肾间质纤维化中的作用机制北大核心CSCD

细胞焦亡是由caspase蛋白酶介导,经GSDMD切割细胞膜成孔,引起细胞破裂死亡、活性促炎因子释放的一种新型的细胞促炎性程序性死亡方式。细胞焦亡分为caspace-1相关的经典途径与caspase-4/5/11相关的非经典途径。细胞焦亡是肾间质纤维化的重要参与者,多种信号刺激激活炎性小体,诱发细胞焦亡,引起炎症反应和免疫细胞、肾固有细胞的相关应答,三者串联形成“焦亡-炎症-纤维化”轴,共同参与肾间质纤维化的发生;细胞焦亡还与自噬相互作用,影响纤维化进程。本文就细胞焦亡的分子机制及其在肾间质纤维化中的作用机制进行概述。     

炎症小体及细胞焦亡在肠道稳态中的研究进展

炎症小体是一种细胞内多蛋白复合物，主要包括NLRP3、AIM2、NLRP6、NLRP12等亚型。识别相关刺激后，炎症小体进行组装并激活caspase-1，激活的caspase-1促进IL-1β和IL-18成熟和分泌。另外，活化的caspase-1也可裂解gasdermin D(GSDMD)，导致特殊形式的细胞死亡——细胞焦亡。肠道稳态在维持机体健康中起重要作用，而炎症小体及细胞焦亡通路在肠道稳态维持中发挥重要作用。本文主要阐述炎症小体及细胞焦亡在肠道稳态维持中的最新研究进展。     

脂多糖通过NLRP3诱导并促进慢性鼻窦炎人鼻黏膜上皮细胞焦亡北大核心CSCD

目的革兰氏阴性菌能够诱发并加重慢性鼻窦炎(CRS)炎症反应,但病理机制有待进一步证实,而细胞焦亡被证实与细菌性炎症反应密切相关,因此本研究重点探讨来源于革兰氏阴性菌的关键成分脂多糖(LPS)是否能够通过诱导并加剧CRS患者鼻黏膜上皮细胞焦亡来促进CRS的炎症进展。方法利用临床上对照组和CRS组患者的鼻黏膜组织,采用IHC检测焦亡相关蛋白的表达。提取并培养正常原代人鼻黏膜上皮细胞(N-HNEpCs)和CRS原代人鼻黏膜上皮细胞(CRS-HNEpCs)。随后将2种细胞分为4组(对照组、LPS 1 mg/L组、LPS 5 mg/L组和LPS 25 mg/L组);CCK-8检测细胞存活率,EthD-I荧光染色结合GSDMD检测细胞焦亡,免疫荧光技术、Western blot、RT-qPCR检测炎性介质IL-18、IL-1β和NLRP3炎症小体(NLRP3、ASC、cleaved Caspase-1)的表达。结果IHC显示CRS患者鼻黏膜组织中NLRP3、cleaved Caspase-1、IL-18和IL-1β蛋白表达相较对照组显著增加(P<0.01)。体外实验结果表明,不同浓度的LPS刺激均可降低N-HNEpCs和CRS-HNEpCs的存活率(P<0.05),并可增加EthD-I荧光染色阳性细胞数和焦亡关键蛋白GSDMD的表达(P<0.05),且呈现出剂量依赖关系;免疫荧光技术、Western blot和RT-qPCR结果均显示5 mg/L LPS刺激后,N-HNEpCs和CRS-HNEpCs内炎性介质IL-18、IL-1β和NLRP3炎症小体的表达显著上调(P<0.05)。结论LPS可通过激活NLRP3炎症小体从而触发正常原代人鼻黏膜上皮细胞焦亡,并可进一步促进CRS原代人鼻黏膜上皮细胞焦亡进展,提示革兰氏阴性菌可能通过诱发鼻黏膜上皮细胞焦亡从而引起并加剧CRS病变。     

细胞焦亡在肾脏炎性损伤中的作用研究进展

细胞焦亡(pyroptoysis)是由活化的caspase-1触发的一种特殊的细胞程序性死亡。肾脏细胞焦亡在肾损伤中发挥着重要的作用。GSDMD切割焦亡关键蛋白caspase-1引起下游炎性反应因子IL-18,IL-1β的成熟和释放引起肾脏炎性反应和细胞焦亡发生。本文从NLRP3激活导致肾脏炎性反应、GSDMD裂解引发细胞焦亡等角度,阐释NLRP3-caspase-1-GSDMD介导的细胞焦亡在肾脏炎性反应中的作用。     

细胞焦亡效应蛋白的作用机制及相关疾病的研究进展

细胞焦亡是一种促炎的程序性细胞死亡方式,并同时具有凋亡和坏死的特点。Toll样受体(Toll like receptors,TLRs)可以感受及识别不同的刺激,并传递信号至依赖半胱氨酸天冬氨酸酶-1(caspase-1)的经典焦亡途径或依赖半胱氨酸天冬氨酸酶-11(caspase-11)的非经典焦亡途径。炎性体在激活信号下的装配是诱导焦亡途径的核心环节,其中NLRP3炎性体是目前研究最多的,是其典型代表。激活的炎性体可以活化炎性caspases,后者进一步促进白细胞介素-1β/18(IL-1β/18)的成熟和释放。焦亡的执行蛋白GSDMD可以在细胞膜上形成膜孔,最终导致细胞渗透溶胀和裂解,同时将炎症因子释放到细胞外,进一步加重炎症反应。     

HIV感染与细胞焦亡

目前艾滋病(AIDS)被认为是一种慢性疾病。炎症和免疫活化在疾病进展中起了重要作用。细胞焦亡是HIV感染过程中造成CD4^+T细胞死亡的主要程序性细胞死亡方式,并伴随着IL-1β等促炎因子和细胞内容物的释放,引起机体炎症反应。细胞焦亡联系起了HIV感染过程中的CD4^+T细胞死亡和炎症反应发生这2个最主要的病理事件。因此,抑制细胞焦亡可能对艾滋患者的治疗有重要意义。本文综述了HIV感染过程中细胞焦亡的发生及其引起的病理性事件,为探索艾滋病患者治疗新策略提供线索。     

GSDMD是细胞焦亡的关键蛋白

细胞焦亡是一种新的细胞死亡模式,该模式不仅能通过依赖于模式识别受体来识别内源性危险信号、病原微生物及其产物刺激炎性小体的作用来激活caspase-1/4/5/11作用于GSDMD;而且使得GSDMD的氨基末端转移至细胞膜上形成的孔隙能允许水分子等物质进入细胞内而引起肿胀及裂解而导致细胞死亡。然而,在细胞焦亡的过程中,关于GSDMD在该过程中的作用以及在相关疾病、肿瘤中的作用仍是个谜。因此,这篇综述的目的是强调了GSDMD引起的焦亡在相关疾病及肿瘤中的作用。     

细胞焦亡：程序性死亡研究新热点

细胞焦亡(Pyroptosis)是一种以促炎性为特点的细胞程序性死亡方式,分为依赖半胱氨酸蛋白酶-1(Caspase-1)的经典细胞焦亡途径和依赖半胱氨酸蛋白酶-4/5/11(Caspase-4/5/11)的非经典细胞焦亡途径。研究表明细胞焦亡广泛参与到多种疾病的发生发展中。最近研究人员发现GSDMD和Pannexin-1可能是介导细胞焦亡的关键物质,但具体机制和相互关系仍有待进一步深入研究。     

细胞焦亡调控与炎症和肿瘤病理机制的关系

细胞焦亡是近年来的研究热点,且在多种疾病中发挥关键作用,在机体炎症反应和免疫反应中普遍存在。该文回顾性综述近年来有关细胞焦亡机制及相关疾病的最新文献,系统而全面地阐述细胞焦亡研究的最新进展。     

柯里拉京抑制LPS和ATP激活的NLRP3炎症小体和巨噬细胞焦亡

目的 探讨柯里拉京对细菌脂多糖(LPS)联合腺嘌呤核苷三磷酸(ATP)诱导的巨噬细胞内NLRP3炎症小体活化和细胞焦亡的调控作用和机制。方法 采用CCK8试剂检测不同浓度柯里拉京对J774A.1细胞活力的影响;碘化丙啶(PI)染色和乳酸脱氢酶(LDH)释放检测柯里拉京对LPS+ATP诱导的细胞死亡的影响。Western blot法检测细胞上清液中炎症小体活化标志物caspase-1 p20(M_r20 000)和成熟IL-1β(M_r17 000)的表达水平,以及检测细胞内NLRP3、ASC、caspase-1、IL-1β前体(pro-IL-1β)和焦亡执行蛋白GSDMD的表达。ELISA检测细胞培养上清液中IL-1β的水平。活性氧(ROS)荧光探针H2DCFDA染色观察柯里拉京对ROS产生的影响。结果 柯里拉京浓度小于40μmol·L^-1时对细胞活性影响较小。柯里拉京减少LPS+ATP刺激的细胞内PI阳性细胞的比例和LDH的释放。柯里拉京抑制LPS+ATP刺激的巨噬细胞内GSDMD蛋白N末端(GSDMD-NT)的表达,以及...     

Caspase-11在固有免疫中的作用

半胱氨酸的天冬氨酸蛋白水解酶Caspase-11与胞内宿主炎症模式识别受体(host pattern recognition receptors,PRR)、炎症小体转接器ASC三部分组成caspase-11炎性小体复合物,被脂多糖的6-乙酰基脂质A识别,进而激活机体固有免疫应答反应.细胞内吞脂多糖(lipopolysaccharide,LPS)后,caspase-11在细胞质内特异识别定位的何种细胞器一直未有明确定论,为精准地靶向定位带来一些困难.脂多糖激活caspase-11可以导致IL-I β/IL-18相关的炎性反应及pannexin-1、GSDMD介导细胞焦亡.Caspase-11的胞内信号靶点探索,将是未来某些疾病治疗新的研究方向,如结肠癌、GSDMD相关的脱毛症等.     

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.     

NF-κB蛋白在柯萨奇病毒B3诱导的病毒性心肌炎小鼠心肌细胞焦亡过程中的调控作用

目的:探讨NF-κB蛋白对柯萨奇病毒B3(CVB3)诱导的病毒性心肌炎小鼠心肌细胞焦亡的调控作用。方法:将编号后的45只雄性BALB/c小鼠根据随机数表法平均分为3组,分别为对照组(normal组)、病毒性心肌炎组(CVB3组)和NF-κB蛋白抑制剂吡咯烷二硫代氨基甲酸(PDTC)处理组(CVB3+PDTC组),每组各15只。7 d后处死各组小鼠,HE染色观察心肌组织内炎症细胞浸润情况;RT-qPCR实验检测心肌组织内CVB3的mRNA表达水平;ELISA实验检测血清中脑钠肽(BNP)和心肌钙蛋白I(cTnI)的表达水平;Western blot实验检测心肌组织内焦亡相关蛋白白细胞介素1β(IL-1β)、gasdermin D(GSDMD)和核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)表达水平,caspase-1/pro-caspase-1比值,以及NF-κB蛋白磷酸化水平。结果:与normal组相比,CVB3组小鼠7 d存活率显著降低,心肌组织内炎症细胞浸润程度显著增加,心肌组织内CVB3的mRNA表达水平显著增加(P<0.05),血清中BNP和cTnI表达水平显著增加(P<0.05),心肌组织内焦亡相关蛋白表达水平、caspase-1/pro-caspase-1比值以及NF-κB蛋白磷酸化水平均显著增加(P<0.05);与CVB3组小鼠相比,CVB3+PDTC组小鼠7 d存活数增加,心肌组织内炎症细胞浸润程度显著降低,心肌组织内CVB3的mRNA表达水平显著降低(P<0.05),血清中BNP和cTnI表达水平显著降低(P<0.05),心肌组织内焦亡相关蛋白表达水平、caspase-1/pro-caspase-1比值以及NF-κB蛋白磷酸化水平均显著降低(P<0.05)。结论:CVB3感染可诱导病毒性心肌炎小鼠心肌组织内焦亡相关蛋白表达水平的上调,且NF-κB信号通路参与心肌组织内细胞焦亡过程的调控。     

Pyroptosis-induced inflammation and tissue damage

Pyroptosis is a programmed necrotic cell death executed by gasdermins, a family of pore-forming proteins. The cleavage of gasdermins by specific proteases enables their pore-forming activity. The activation of the prototype member of the gasdermin family, gasdermin D (GSDMD), is linked to innate immune monitoring by inflammasomes. Additional gasdermins such as GSDMA, GSDMB, GSDMC, and GSDME are activated by inflammasome-independent mechanisms. Pyroptosis is emerging as a key host defense strategy against pathogens. However, excessive pyroptosis causes cytokine storm and detrimental inflammation leading to tissue damage and organ dysfunction. Consequently, dysregulated pyroptotic responses contribute to the pathogenesis of various diseases, including sepsis, atherosclerosis, acute respiratory distress syndrome, and neurodegenerative disorders. This review will discuss the inflammatory consequences of pyroptosis and the mechanisms of pyroptosis-induced tissue damage and disease pathogenesis.     

骨关节炎形成过程中细胞焦亡的作用与机制

背景:研究发现,在骨关节炎的病理进展中,细胞焦亡参与其中并发挥作用。目的:了解当前细胞焦亡在骨关节炎中的最新研究进展,并探讨他们的关系,为骨关节炎的研究和诊疗提供新的靶点。方法:从CNKI、万方数据、维普、ScienceDirect、Nature、Springer、PubMed等数据库进行相关文献的检索。中文检索词:骨关节炎、细胞焦亡、核苷酸结合寡聚化结构域样受体蛋白3、核因子κB、半胱天冬酶、白细胞介素、gasdermin D;英文检索词:osteoarthritis(OA),pyroptosis,nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),Nuclear factor kappa B(NF-κB),caspase,interleukin(IL),gasdermin D(GSDMD)。从被检索出的文献中根据入选标准进行筛选,最终纳入相关文献61篇。结果与结论:细胞焦亡与骨关节炎中的软骨降解、炎症反应和滑膜的破坏等都有一定的关系。在细胞焦亡激活过程中,所涉及到的一些蛋白和细胞因子均存在差异性表达,如NLRs、caspases、白细胞介素和GSDMD等,虽然已有研究显示它们与骨关节炎的病理发展存在着一定的关系,但其在骨关节炎中的作用机制还未完全了解。     

GSDMD-mediated NETosis promotes the development of acute respiratory distress syndrome

Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N-terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD-deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS-induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co-cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS.     

Cholecalciferol pretreatment ameliorates ischemia/reperfusion-induced acute kidney injury through inhibiting ROS production,NF-κB pathway and pyroptosis

Acute kidney injury (AKI) is a common complication in patients with potentially life-threatening diseases, and it is also usually associated with unacceptable morbidity and mortality rates. Therefore, new and efficient therapies are urgently required to relieve AKI. It is well known that, reactive oxygen species (ROS), the NF-κB signaling pathways and pyroptosis are involved in AKI induced by ischemia/reperfusion (I/R). The present study seeks to further confirm the internal relationship between vitamin D deficiency and I/R-induced AKI in patients, and to explore the underlying mechanisms of ROS, NF-κB signaling pathways and pyroptosis in the renal ischemia-reperfusion injury, as well as investigating the protective role of cholecalciferol. Patients with vitamin D deficiency show worse renal function reflected by postoperative glomerular filtration rate (GFR) and more release of proinflammatory cytokine IL-1β and IL-18. Renal cell injury and renal dysfunction induced by I/R surgery were attenuated in the ICR mice administered with cholecalciferol. Cholecalciferol reduced ROS production, suppressed activated NF-κB signaling, and inhibited gasdermin D (GSDMD, a pyroptosis execution protein)-mediated pyroptosis. Cholecalciferol therefore has potential, as a clinical drug, to protect renal function in I/R-induced AKI through reducing ROS production, NF-κB activation and GSDMD-mediated pyroptosis.