Pyroptosis and its role in cancer

Programmed cell death (PCD) is mediated by specific genes that encode signals. It can balance cell survival and death. Pyroptosis is a type of inflammatory, caspase-dependent PCD mediated by gasdermin proteins, which function in pore formation, cell expansion, and plasma membrane rupture, followed by the release of intracellular contents. Pyroptosis is mediated by caspase-1/3/4/5/11 and is primarily divided into the classical pathway, which is dependent on caspase-1, and the non-classical pathway, which is dependent on caspase-4/5/11. Inflammasomes play a vital role in these processes. The various components of the pyroptosis pathway are related to the occurrence, invasion, and metastasis of tumors. Research on pyroptosis has revealed new options for tumor treatment. This article summarizes the recent research progress on the molecular mechanism of pyroptosis, the relationship between the various components of the pyroptosis pathway and cancer, and the applications and prospects of pyroptosis in anticancer therapy.     

焦亡在肿瘤治疗中作用的研究进展

细胞焦亡是一种伴随炎症反应的程序性细胞死亡,主要通过激活炎性半胱氨酸蛋白酶Caspase-1/4/5/11切割GSDMD或激活凋亡半胱氨酸蛋白酶Caspase-3切割GSDME两种途径被触发.细胞焦亡参与多种疾病的发生发展.近年来,焦亡在肿瘤治疗中的意义得到了广泛关注,积累了诸多新成果,形成了一些新见解.本文谨就此进行...     

Gasdermin D-mediated hepatocyte pyroptosis expands inflammatory responses that aggravate acute liver failure by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages

BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death. However, the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(sh RNA) was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1) and its receptor CC chemokine receptor-2(CCR2) in vitro. For in vivo experiments, we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALFpatients and a hepatocyte injury model increased significantly. The level of GSDMD-N protein increased most obviously(P 0.001). In vitro, downregulation of GSDMD by sh RNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P 0.01). In vivo, GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P 0.001). Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1β and IL-18, GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death. However, this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF, recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses. GSDMD knockout can reduce hepatocyte death and inflammatory responses, thus alleviating ALF.     

The Gasdermin‐D pore acts as a conduit for IL‐1β secretion in mice

The pro‐inflammatory cytokine IL‐1β is well known for its role in host defense and the initiation of potent inflammatory responses. It is processed from its inactive pro‐form by the inflammatory caspase‐1 into its mature bioactive form, which is then released from the cell via an unconventional secretion mechanism. Recently, gasdermin‐D has been identified as a new target of caspase‐1. After proteolytical cleavage of gasdermin‐D, the N‐terminal fragment induces pyroptosis, a lytic cell death, by forming large permeability pores in the plasma membrane. Here we show using the murine system that gasdermin‐D is required for IL‐1β secretion by macrophages, dendritic cells and partially in neutrophils, and that secretion is a cell‐lysis‐independent event. Liposome transport assays in vitro further demonstrate that gasdermin‐D pores are large enough to allow the direct release of IL‐1β. Moreover, IL‐18 and other small soluble cytosolic proteins can also be released in a lysis‐independent but gasdermin‐D‐dependent mode, suggesting that the gasdermin‐D pores allow passive the release of cytosolic proteins in a size‐dependent manner.     

细胞焦亡在非小细胞肺癌发生发展和治疗预后中作用及机制的研究进展北大核心

细胞焦亡是一种促炎性程序性细胞死亡(programmed cell death,PCD),通过切割活化后的GSDMD、GSDME、GSDMB等Gasdermin家族蛋白在质膜上成孔,释放IL-18和IL-1β等促炎因子,具有比凋亡更快的细胞杀伤作用,在肿瘤研究中越来越受到关注。对于非小细胞肺癌(non-small cell lung cancer,NSCLC),细胞焦亡可通过调节肿瘤微环境影响NSCLC的发生发展,也可以通过调节抗肿瘤免疫影响NSCLC的治疗预后。一些中医药、化疗药、免疫治疗可通过细胞焦亡发挥抗肿瘤作用,增强细胞焦亡后也可以提高这些药物敏感性;但细胞焦亡过强会损伤正常组织,是一些药物产生毒副作用的原因。本文通过探讨细胞焦亡在NSCLC发生发展、治疗预后中的作用,为NSCLC的临床诊疗提供新思路。     

电针“百会”“人中”对脑缺血再灌注损伤模型大鼠脑脊液炎症因子及皮质缺血区脑组织GSDMD表达的影响

目的探讨电针百会人中穴治疗脑缺血再灌注损伤(CIRI)的疗效及可能作用机制。方法36只雄性SD大鼠随机分为假手术组、模型组和电针组,每组12只。除假手术组外其余大鼠采用大脑中动脉线栓阻断法制备CIRI大鼠模型。造模24 h后对电针组大鼠行电针干预,穴取百会人中,频率15 Hz、强度为1 mA的连续波,每天1次,每次20 min,共5天。用Longa法评定各组大鼠神经功能损伤程度;TTC染色法测定大鼠脑梗死体积,HE染色观察脑组织病理形态改变;ELISA法检测脑脊液白细胞介素1β(IL-1β)、白细胞介素6 (IL-6)、白细胞介素18 (IL-18)水平;逆转录聚合酶链反应和Western blotting法分别检测皮质缺血区脑组织Gasdermin D (GSDMD) mRNA和Gasdermin D蛋白的氮端(GSDMD-N)蛋白表达。结果与假手术组比较,模型组大鼠神经功能评分明显上升、脑梗死体积明显增加,脑脊液IL-1β、IL-6和IL-18含量明显增加,皮质缺血区脑组织GSDMD mRNA及GSDMD-N蛋白表达水平明显增高(P<0.05或P<0.01);HE染色结果显示,模型组大鼠脑组织神经元排列紊乱,部分神经细胞消失,胞核固缩,结构不完整。与模型组比较,电针组大鼠神经功能评分下降、脑梗死体积减小,脑脊液IL-6和IL-18含量明显减少,GSDMD mRNA及GSDMD-N蛋白表达水平降低(P<0.05或P<0.01);大鼠大脑皮质神经元变性及神经细胞数量丢失程度均较模型组有所减轻。结论电针百会人中穴能使CIRI模型大鼠脑梗死体积减小,改善大鼠神经功能,其机制可能与下调脑脊液炎症因子和皮质缺血区脑组织细胞焦亡底物蛋白GSDMD表达有关。     

mtDNA Activates cGAS Signaling and Suppresses the YAP-Mediated Endothelial Cell Proliferation Program to Promote Inflammatory Injury

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Pyroptosis and the cellular consequences of gasdermin pores

The family of gasdermin proteins plays a key role in the host response against external and internal pathogenic signals by mediating the form of inflammatory regulated cell death known as pyroptosis. One of the most well-studied gasdermins within innate immunity is gasdermin D, which is cleaved, oligomerizes, and forms plasma membrane pores. Gasdermin D pores lead to a number of downstream cellular consequences including plasma membrane rupture, or cell lysis. In this review, we describe mechanisms of activation for each of the gasdermins, their cell type specificity and some disease associations. We then discuss downstream consequences of gasdermin pore formation, including cellular mechanisms of membrane repair. Finally, we present some important next steps to better understand pyroptosis and the cellular consequences of gasdermin pore formation.