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 me...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(shRNA)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 ALF patients 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 shRNA 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)-1βand 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.展开更多
细胞焦亡是细胞促炎程序性死亡,其强弱程度依赖于胱天蛋白酶(Caspases)活性。Caspases通过切割Gasdermin家族蛋白使其形成无活性的C端片段和有活性的N端片段,后者移位到膜上并形成穿孔,导致水分渗透和细胞肿胀并释放炎性因子,继而引发...细胞焦亡是细胞促炎程序性死亡,其强弱程度依赖于胱天蛋白酶(Caspases)活性。Caspases通过切割Gasdermin家族蛋白使其形成无活性的C端片段和有活性的N端片段,后者移位到膜上并形成穿孔,导致水分渗透和细胞肿胀并释放炎性因子,继而引发细胞焦亡。细胞焦亡的不同信号通路机制在各类疾病的发生发展过程中发挥着重要作用。多糖作为生物大分子对细胞核因子-κB、核苷酸结合寡聚化结构域样受体蛋白3(NOD-like receptor protein 3,NLRP3)及活性氧等信号分子均具有调节作用。但多糖能否通过影响相关信号通路达到抑制或激活细胞焦亡的作用有待进一步研究。本文综述细胞焦亡相关信号通路、细胞焦亡在疾病中的作用及多糖在细胞焦亡信号通路调节中的作用,旨在对多糖在细胞焦亡中的潜在作用进行探讨,为进一步开发功能性多糖提供新的思路。展开更多
基金Supported by the National Natural Science Foundation of China,No.81570543 and No.81560104
文摘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(shRNA)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 ALF patients 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 shRNA 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)-1βand 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.
文摘细胞焦亡是细胞促炎程序性死亡,其强弱程度依赖于胱天蛋白酶(Caspases)活性。Caspases通过切割Gasdermin家族蛋白使其形成无活性的C端片段和有活性的N端片段,后者移位到膜上并形成穿孔,导致水分渗透和细胞肿胀并释放炎性因子,继而引发细胞焦亡。细胞焦亡的不同信号通路机制在各类疾病的发生发展过程中发挥着重要作用。多糖作为生物大分子对细胞核因子-κB、核苷酸结合寡聚化结构域样受体蛋白3(NOD-like receptor protein 3,NLRP3)及活性氧等信号分子均具有调节作用。但多糖能否通过影响相关信号通路达到抑制或激活细胞焦亡的作用有待进一步研究。本文综述细胞焦亡相关信号通路、细胞焦亡在疾病中的作用及多糖在细胞焦亡信号通路调节中的作用,旨在对多糖在细胞焦亡中的潜在作用进行探讨,为进一步开发功能性多糖提供新的思路。
