NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous chemicals.Its activation results in the release of cytokines such as IL-1β and IL-18...NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous chemicals.Its activation results in the release of cytokines such as IL-1β and IL-18,as well as Gasdermin D which eventually causes pyroptosis.The activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and mechanisms.Its excessive activation can lead to a persistent inflammatory response,which is linked to the onset and progression of severe illnesses.Recent studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation process.In this review,we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation,focusing on the subcellular localization of NLRP3 and the associated regulatory mechanisms.We aim to provide a comprehensive understanding of the dynamic transportation,activation,and degradation processes of NLRP3.展开更多
The covalently closed circular DNA(cccDNA)of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases,including liver fibrosis.Stimulator of interferon genes(STING),a...The covalently closed circular DNA(cccDNA)of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases,including liver fibrosis.Stimulator of interferon genes(STING),a master regulator of DNA-mediated innate immune activation,is a potential therapeutic target for viral infection and virus-related diseases.In this study,agonist-induced STING signaling activation in macrophages was revealed to inhibit cccDNA-mediated transcription and HBV replication via epigenetic modification in hepatocytes.Notably,STING activation could efficiently attenuate the severity of liver injury and fibrosis in a chronic recombinant cccDNA(rcccDNA)mouse model,which is a proven suitable research platform for HBV-induced fibrosis.Mechanistically,STING-activated autophagic flux could suppress macrophage inflammasome activation,leading to the amelioration of liver injury and HBV-induced fibrosis.Overall,the activation of STING signaling could inhibit HBV replication through epigenetic suppression of cccDNA and alleviate HBV-induced liver fibrosis through the suppression of macrophage inflammasome activation by activating autophagic flux in a chronic HBV mouse model.This study suggests that targeting the STING signaling pathway may be an important therapeutic strategy to protect against persistent HBV replication and HBV-induced fibrosis.展开更多
文摘NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous chemicals.Its activation results in the release of cytokines such as IL-1β and IL-18,as well as Gasdermin D which eventually causes pyroptosis.The activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and mechanisms.Its excessive activation can lead to a persistent inflammatory response,which is linked to the onset and progression of severe illnesses.Recent studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation process.In this review,we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation,focusing on the subcellular localization of NLRP3 and the associated regulatory mechanisms.We aim to provide a comprehensive understanding of the dynamic transportation,activation,and degradation processes of NLRP3.
基金This work was supported by grants from the National Natural Science Foundation of China(C31872731,C32070910,C31470839)Zhengyi Scholar Foundation of School of Basic Medical Sciences,Fudan University(S25-01).
文摘The covalently closed circular DNA(cccDNA)of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases,including liver fibrosis.Stimulator of interferon genes(STING),a master regulator of DNA-mediated innate immune activation,is a potential therapeutic target for viral infection and virus-related diseases.In this study,agonist-induced STING signaling activation in macrophages was revealed to inhibit cccDNA-mediated transcription and HBV replication via epigenetic modification in hepatocytes.Notably,STING activation could efficiently attenuate the severity of liver injury and fibrosis in a chronic recombinant cccDNA(rcccDNA)mouse model,which is a proven suitable research platform for HBV-induced fibrosis.Mechanistically,STING-activated autophagic flux could suppress macrophage inflammasome activation,leading to the amelioration of liver injury and HBV-induced fibrosis.Overall,the activation of STING signaling could inhibit HBV replication through epigenetic suppression of cccDNA and alleviate HBV-induced liver fibrosis through the suppression of macrophage inflammasome activation by activating autophagic flux in a chronic HBV mouse model.This study suggests that targeting the STING signaling pathway may be an important therapeutic strategy to protect against persistent HBV replication and HBV-induced fibrosis.
