程序性细胞坏死及细胞焦亡信号通路研究进展概述

细胞死亡是生命活动中一个非常重要的事件,真核生物可因物理损伤刺激导致细胞死亡,因特异信号通路介导的程序性细胞死亡近年来得到越来越多的关注。目前程序性细胞死亡主要存在以下3种方式:凋亡(apoptosis)、程序性坏死(necroptosis)、细胞焦亡(pyroptosis)。程序性坏死和细胞焦亡是近年来才发现的新的细胞程序性死亡方式,在细菌或病毒感染宿主细胞过程中起着关键作用。这两种细胞死亡都是细胞裂解型死亡,但其信号通路存在明显差异。本文就这两种程序性细胞死亡的形态学特征、信号转导通路及其在病原体感染过程中的作用等方面的研究进展作一综述。     

炎症反应在细胞焦亡和动脉粥样硬化之间的作用

心血管疾病是全球慢性非传染性疾病中死亡率最高的一类疾病，而动脉粥样硬化（AS）在心血管疾病的发生发展中扮演了重要的角色。炎症反应与动脉粥样硬化形成密切相关，而其又广泛参与细胞焦亡过程。核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）、适配器凋亡相关微粒蛋白（apoptosis-associated speck-like protein containing CARD，ASC）以及Caspase-1等细胞焦亡的重要功能分子均参与AS形成，细胞焦亡的过程中伴随白细胞介素等炎症介质的产生及释放，而炎症反应又可反过来促进细胞焦亡的发生发展。我们分别从炎症反应在动脉粥样硬化、细胞焦亡形成中的作用，炎症反应在这两者之间的桥梁作用等3个方面进行综述。     

Inflammatory cell death in intestinal pathologies

The intestinal tract is a site of intense immune cell activity that is poised to mount an effective response against a pathogen and yet maintain tolerance toward commensal bacteria and innocuous dietary antigens. The role of cell death in gut pathologies is particularly important as the intestinal epithelium undergoes self-renewal every 4-7 days through a continuous process of cell death and cell division. Cell death is also required for removal of infected, damaged, and cancerous cells. Certain forms of cell death trigger inflammation through release of damage-associated molecular patterns. Further, molecules involved in cell death decisions also moonlight as critical nodes in immune signaling. The manner of cell death is, therefore, highly instructive of the immunological consequences that ensue. Perturbations in cell death pathways can impact the regulation of the immune system with deleterious consequences. In this review, we discuss the various forms of cell death with a special emphasis on lytic cell death pathways of pyroptosis and necroptosis and their implications in inflammation and cancer in the gut. Understanding the implications of distinct cell death pathways will help in the development of therapeutic interventions in intestinal pathologies.     

Pyroptosis in defense against intracellular bacteria

Pathogenic microbes invade the human body and trigger a host immune response to defend against the infection. In response, host-adapted pathogens employ numerous virulence strategies to overcome host defense mechanisms. As a result, the interaction between the host and pathogen is a dynamic process that shapes the evolution of the host's immune response. Among the immune responses against intracellular bacteria, pyroptosis, a lytic form of cell death, is a crucial mechanism that eliminates replicative niches for intracellular pathogens and modulates the immune system by releasing danger signals. This review focuses on the role of pyroptosis in combating intracellular bacterial infection. We examine the cell type specific roles of pyroptosis in neutrophils and intestinal epithelial cells. We discuss the regulatory mechanisms of pyroptosis, including its modulation by autophagy and interferon-inducible GTPases. Furthermore, we highlight that while host-adapted pathogens can often subvert pyroptosis, environmental microbes are effectively eliminated by pyroptosis.     

Pyroptosis in cardiovascular diseases: Pumping gasdermin on the fire

Pyroptosis is a form of programmed cell death associated with activation of inflammasomes and inflammatory caspases, proteolytic cleavage of gasdermin proteins (forming pores in the plasma membrane), and selective release of proinflammatory mediators. Induction of pyroptosis results in amplification of inflammation, contributing to the pathogenesis of chronic cardiovascular diseases such as atherosclerosis and diabetic cardiomyopathy, and acute cardiovascular events, such as thrombosis and myocardial infarction. While engagement of pyroptosis during sepsis-induced cardiomyopathy and septic shock is expected and well documented, we are just beginning to understand pyroptosis involvement in the pathogenesis of cardiovascular diseases with less defined inflammatory components, such as atrial fibrillation. Due to the danger that pyroptosis represents to cells within the cardiovascular system and the whole organism, multiple levels of pyroptosis regulation have evolved. Those include regulation of inflammasome priming, post-translational modifications of gasdermins, and cellular mechanisms for pore removal. While pyroptosis in macrophages is well characterized as a dramatic pro-inflammatory process, pyroptosis in other cell types within the cardiovascular system displays variable pathways and consequences. Furthermore, different cells and organs engage in local and distant crosstalk and exchange of pyroptosis triggers (oxidized mitochondrial DNA), mediators (IL-1β, S100A8/A9) and antagonists (IL-9). Development of genetic tools, such as Gasdermin D knockout animals, and small molecule inhibitors of pyroptosis will not only help us fully understand the role of pyroptosis in cardiovascular diseases but may result in novel therapeutic approaches inhibiting inflammation and progression of chronic cardiovascular diseases to reduce morbidity and mortality from acute cardiovascular events.     

焦亡信号通路炎症小体与中枢神经系统疾病研究进展

焦亡是一种新发现并证实与炎症相关的细胞死亡方式,其特征为依赖于半胱天冬氨酸蛋白酶-1(caspase-1)的细胞程序性死亡,并伴有促炎症因子的释放,主要为白细胞介素1β和IL-18.虽然焦亡与坏死和凋亡有相似之处,但它们是迥然不同的生物学过程.越来越多的研究发现,焦亡相关信号通路在中枢神经系统疾病中起重要作用,包括急性脑感染、神经变性疾病、急性无菌性脑损伤和慢性无菌性中枢神经系统炎症.     

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation,autophagy, and cell death

Stimulator of interferons genes (STING) is an adaptor protein that plays a critical role in the secretion of type I interferons and pro‐inflammatory cytokines in response to cytosolic nucleic acid. Recent research indicates the involvement of the STING pathway in uncontrolled inflammation, sepsis, and shock. STING signaling is significantly up‐regulated in human sepsis, and STING agonists are suggested to contribute to the pathogenesis of sepsis and shock. Nevertheless, little is known about the consequences of activated STING‐mediated signaling during sepsis. It has been shown that aberrant activation of the STING‐dependent way can result in increased inflammation, type I interferons responses, and cell death (including apoptosis, necroptosis, and pyroptosis). In addition, autophagy modulation has been demonstrated to protect against multiple organs injuries in animal sepsis model. However, impaired autophagy may contribute to the aberrant activation of STING signaling, leading to uncontrolled inflammation and cell death. Here we present a comprehensive review of recent advances in the understanding of STING signaling, focusing on the regulatory mechanisms and the roles of this pathway in sepsis.     

Microparticles and autophagy: a new frontier in the understanding of atherosclerosis in rheumatoid arthritis

Microparticles (MPs) are small membrane vesicles released by many cell types under physiological and pathological conditions. In the last years, these particles were considered as inert cell debris, but recently many studies have demonstrated they could have a role in intercellular communication. Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, and autoimmune diseases, such as rheumatoid arthritis (RA). RA is an autoimmune systemic inflammatory disease characterized by chronic synovial inflammation, resulting in cartilage and bone damage with accelerated atherosclerosis increasing mortality. According to the literature data, also MPs could have a role in endothelial dysfunction, contributing to atherosclerosis in RA patients. Moreover many researchers have shown that a dysregulated autophagy seems to be involved in endothelial dysfunction. Autophagy is a reparative process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. It has been shown in many works that basal autophagy is essential to proper vascular function. Taking into account these considerations, we hypothesized that in RA patients MPs could contribute to atherosclerosis process by dysregulation of endothelial autophagy process.     

The Role of Cell Death in the Pathogenesis of SLE: Is Pyroptosis the Missing Link?

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of antinuclear antibodies (ANAs) in association with systemic inflammation and organ damage. In addition to genetic factors, a contribution of infection to disease induction has been proposed. In the pathogenesis of lupus, immune complexes of ANAs with nuclear antigens can form and both deposit in the tissue and stimulate cytokine production to intensify inflammation. As such, the extracellular release of nuclear antigens to form pathogenic immune complexes is an important step in the pathway to disease. This release has been considered the consequence of cell death, with apoptotic cells the relevant source of nuclear material. While apoptosis could serve this role, other death forms may act similarly. Among these death forms, pyroptosis, which can be induced by inflammasome activation during infection, has features suggesting involvement in lupus. Thus, unlike apoptosis, pyroptosis is a pro‐inflammatory process. Furthermore, pyroptosis leads to the release of intracellular contents including HMGB1 and ATP, both of which can act as DAMPs (death associated molecular patterns) to stimulate further inflammation. Importantly, pyroptosis can lead to the release of intact nuclei, suggesting a relationship to events in the formation of LE cells. While the role of pyroptosis in SLE is hypothetical at this time, further analysis of this death form should provide new insights into lupus pathogenesis and provide the missing link between infection and the initiation of lupus by products of dead and dying cells.     

细胞焦亡:一种新的细胞死亡方式

细胞焦亡是近年来发现并证实的一种新的程序性细胞死亡方式,其特征为依赖于半胱天冬酶-1(caspase-1),并伴有大量促炎症因子的释放.细胞焦亡的形态学特征、发生及调控机制等均不同于凋亡、坏死等其他细胞死亡方式.研究表明,细胞焦亡广泛参与感染性疾病、神经系统相关疾病和动脉粥样硬化性疾病等的发生发展,并发挥重要作用.对细...     

细胞自噬与动脉粥样硬化关系的研究进展

自噬是一种降解病原体和相关细胞器尤其是损伤的线粒体的分子机制,自噬也可清除其他的细胞成分,例如炎症和细胞因子,这为抗炎症提供了重要的途径.相关研究发现,自噬的产生或降解能够影响动脉粥样硬化斑块的发展过程.因此,在疾病出现时,自噬的调节对于疾病治疗的靶点具有重要的意义.然而,在正常情况和炎症反应时,自噬的调节方式是多方面的.这些错综复杂的改变是通过炎症和环境刺激所产生的,这对于了解和揭示自噬调节的炎症和提供相应的治疗方案是必不可少的.因而人了解自噬的分子机制,以及血管内皮细胞、血管平滑肌细胞、巨噬细胞自噬在动脉粥样硬化中起到的作用对于疾病的发展和靶向治疗具有重要意义.     

心肌缺血再灌注损伤中细胞焦亡的研究进展

细胞焦亡是近年来发现并被证实的一种新的细胞程序性死亡方式,它的特征是依赖半胱氨酸天冬氨酸酶1(cysteinyl aspartate specific proteinase 1,caspase-1)并伴随大量炎症因子的释放。细胞焦亡参与了包括感染性疾病在内的多种疾病的病理生理过程。作为一种新的调节性细胞死亡方式,近年来...     

Evidence for apoptosis in human atherogenesis and in a rat vascular injury model.

Apoptosis is a physiological cell death process important for normal development and involved in many pathological conditions. In atherosclerosis, pathological accumulation of cells in the intima has been attributed to the migration and proliferation of smooth muscle cells, macrophages, and lymphocytes. In this report, we explored the possibility that apoptosis may also contribute to the pathogenesis of this disease. We examined 35 human atherosclerotic lesion samples and identified a substantial number of cells undergoing apoptosis in 25 of the samples. Furthermore, in a rat vascular injury model, apoptotic cells were specifically identified in the neointima. The presence of apoptotic cells was demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, nuclear staining with propidium iodide, and electron microscopy. Immunostaining with cell-type-specific markers and subsequent terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling analysis on the same sample revealed that the majority of the apoptotic cells were modulated smooth muscle cells as well as macrophages. These results indicate that apoptosis occurs in cells of the injured blood vessel as well as the advanced atherosclerotic lesion and that physiological cell death may have an important role in determining the course of atherogenesis.     

ERK and Akt signaling pathways are involved in advanced glycation end product-induced autophagy in rat vascular smooth muscle cells

Advanced glycation end products (AGEs) play an important role in the proliferation of vascular smooth muscle cells (VSMCs) and accelerate atherosclerosis in diabetic patients. Autophagy, a life-sustaining process, is stimulated in atherosclerotic plaques by oxidized lipids, inflammation and metabolic stress conditions. In our studies, we utilized MTT assays to show that autophagy is involved in AGE-induced proliferation of VSMCs. Furthermore, treatment with AGEs (100 μg/ml) could induce autophagy in a time- and dose-dependent manner in rat aortic VSMCs. These results were further substantiated by electron microscopy and immunofluorescence imaging. Treatment with AGEs activated ERK, JNK and p38/MAPK, but inhibited Akt. Pretreatment with an ERK inhibitor and an Akt activator inhibited AGE-induced autophagy, demonstrating that AGEs induce autophagy in VSMCs through the ERK and Akt signaling pathways. In addition, RNA interference of RAGE decreased autophagy, indicating that RAGE is pivotal in the process of AGE-induced autophagy. Therefore, AGE-induced autophagy contributes to the process of AGE-induced proliferation of VSMCs, which is related to atherosclerosis in diabetes.     

Molecular mechanisms and functions of pyroptosis,inflammatory caspases and inflammasomes in infectious diseases

Cell death is a fundamental biological phenomenon that is essential for the survival and development of an organism. Emerging evidence also indicates that cell death contributes to immune defense against infectious diseases. Pyroptosis is a form of inflammatory programmed cell death pathway activated by human and mouse caspase-1, human caspase-4 and caspase-5, or mouse caspase-11. These inflammatory caspases are used by the host to control bacterial, viral, fungal, or protozoan pathogens. Pyroptosis requires cleavage and activation of the pore-forming effector protein gasdermin D by inflammatory caspases. Physical rupture of the cell causes release of the pro-inflammatory cytokines IL-1β and IL-18, alarmins and endogenous danger-associated molecular patterns, signifying the inflammatory potential of pyroptosis. Here, we describe the central role of inflammatory caspases and pyroptosis in mediating immunity to infection and clearance of pathogens.     

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。     

Sevoflurane Combined with ATP Activates Caspase-1 and Triggers Caspase-1-Dependent Pyroptosis in Murine J774 Macrophages

Sevoflurane is one of the most commonly used volatile anesthetics. Recent studies have shown that sevoflurane plays an important role in modulation of inflammation and immunity. However, little is known about the related molecular mechanisms. This study was designed to investigate the effects and mechanisms of sevoflurane on inflammatory cell death pyroptosis in the murine macrophage cell line J774 cells. Sevoflurane combined with ATP could increase the level of activated caspase-1, pyroptosis, and reactive oxygen species (ROS). Furthermore, treatment of cells with the caspase-1 inhibitor Ac-YVAD-CMK dramatically decreased the percentage of pyroptosis. In addition, inhibition of ROS with N-acetyl-l-cysteine or diphenyleneiodonium significantly reduced the activated levels of caspase-1. These results demonstrated that sevoflurane combined with ATP could activate caspase-1 and trigger caspase-1-dependent pyroptosis through the modulation of ROS production.     

The effect of cell death in the initiation of lupus nephritis

Cell death and the release of chromatin have been demonstrated to activate the immune system producing autoantibodies against nuclear antigens in patients with systemic lupus erythematosus (SLE). Apoptosis, necrosis, necroptosis, secondary necrosis, autophagy and the clearance of dying cells by phagocytosis are processes believed to have a role in tolerance avoidance, activation of autoimmune lymphocytes and tissue damage by effector cells. The released chromatin not only activates the immune system; it also acts as antigen for the autoantibodies produced, including anti-dsDNA antibodies. The subsequent immune complex formed is deposited within the basement membranes and the mesangial matrix of glomeruli. This may be considered as an initiating event in lupus nephritis. The origin of the released chromatin is still debated, and the possible mechanisms and cell sources are discussed in this study.     

细胞自噬在宫颈癌中的相关研究进展

细胞自噬指细胞利用溶酶体降解细胞质中错误折叠的蛋白质及受损细胞器等,重新利用降解物质及胞内有害物质的过程,以维持细胞内环境稳定。正常状态下细胞的自噬维持在低水平,当细胞处在不利因素条件下,自噬也会被激活应对不利因素。自噬在肿瘤发生、发展、转移、复发、药物抵抗等方面有着重要作用,但自噬在这些方面的详细机制仍不清楚。我们在文中对宫颈癌细胞中自噬相关基因的表达情况进行了阐述,自噬治疗在宫颈癌中具有重要的应用前景。     

PM2.5 induced lung injury through upregulating ROS-dependent NLRP3 Inflammasome-Mediated Pyroptosis

The main cause of air pollution is PM_2.5, which directly causes lung injury through respiration. Oxidative stress and inflammation are considered to be the key mechanism of cell damage. Pyroptosis is a process of the programmed death of inflammatory cells and as a dangerous endogenous signal, it is widely involved in different inflammatory diseases. However, few studies have been conducted on PM_2.5 exposure and cell pyroptosis. In this study, we aimed to investigate the effect of PM_2.5 on apoptosis, pyroptosis and cell cycle arrest regulated by reactive oxygen species production. Balb/c mice were exposed to PM_2.5 dynamically and verified by the RAW264.7 cells in vitro. The results showed the activation of NF-κB and NLRP3 inflammasome and the release of IL-1β and reactive oxygen species were caused by exposure to PM_2.5. The maturation of IL-1β relied on Caspase-1, and the active Caspase-1 was related to cell pyroptosis. Oxidative stress, inflammation, apoptosis and pyroptosis all affected the cell cycle. This study describes a potentially important mechanism of PM_2.5-induced lung damage that PM_2.5 promotes lung injury via upregulating ROS-NLRP3-mediated the RAW264.7 cells pyroptosis.