The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3,adapter protein ASC,and inflammatory protease caspase-1 that responds to microbial infection,endogenous d...The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3,adapter protein ASC,and inflammatory protease caspase-1 that responds to microbial infection,endogenous danger signals,and environmental stimuli.The assembled NLRP3 inflammasome can activate the protease caspase‐1 to induce gasdermin D-dependent pyroptosis and facilitate the release of IL-1β and IL-18,which contribute to innate immune defense and homeostatic maintenance.However,aberrant activation of the NLRP3 inflammasome is associated with the pathogenesis of various inflammatory diseases,such as diabetes,cancer,and Alzheimer’s disease.Recent studies have revealed that NLRP3 inflammasome activation contributes to not only pyroptosis but also other types of cell death,including apoptosis,necroptosis,and ferroptosis.In addition,various effectors of cell death have been reported to regulate NLRP3 inflammasome activation,suggesting that cell death is closely related to NLRP3 inflammasome activation.In this review,we summarize the inextricable link between NLRP3 inflammasome activation and cell death and discuss potential therapeutics that target cell death effectors in NLRP3 inflammasome-associated diseases.展开更多
Cell death is a fundamental physiological process in all living organisms.Its roles extend from embryonic development,organ maintenance,and aging to the coordination of immune responses and autoimmunity.In recent year...Cell death is a fundamental physiological process in all living organisms.Its roles extend from embryonic development,organ maintenance,and aging to the coordination of immune responses and autoimmunity.In recent years,our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially.Different modalities of what has become known as‘programmed cell death’have been described,and some key players in these processes have been identified.We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death.These studies have highlighted the complex mechanisms tipping the balance between different cell fates.Here,we summarize the latest discoveries in the three most well understood modalities of cell death,namely,apoptosis,necroptosis,and pyroptosis,highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.展开更多
Pyroptosis is the process of inflammatory cell death.The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection.Excessive pyroptosis,however,leads to s...Pyroptosis is the process of inflammatory cell death.The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection.Excessive pyroptosis,however,leads to several inflammatory diseases,including sepsis and autoimmune disorders.Pyroptosis can be canonical or noncanonical.Upon microbe infection,the canonical pathway responds to pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs),while the noncanonical pathway responds to intracellular lipopolysaccharides(LPS) of Gram-negative bacteria.The last step of pyroptosis requires the cleavage of gasdermin D(GsdmD) at D275(numbering after human GSDMD) into N-and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11(caspase 4/5 in humans,caspase 11 in mice) in the noncanonical pathway.Upon cleavage,the N-terminus of GsdmD(GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1β and IL-18 and disturbs the regulation of ions and water,eventually resulting in strong inflammation and cell death.Since GsdmD is the effector of pyroptosis,promising inhibitors of GsdmD have been developed for inflammatory diseases.This review will focus on the roles of GsdmD during pyroptosis and in diseases.展开更多
OBJECTIVE To investigate the anti-pyroptotic effects of melatonin in atherosclerotic endothelium and to elucidate the potential mechanisms.METHODS ApoE-/-mice were randomly divid.ed into four groups(n=8):the normal-di...OBJECTIVE To investigate the anti-pyroptotic effects of melatonin in atherosclerotic endothelium and to elucidate the potential mechanisms.METHODS ApoE-/-mice were randomly divid.ed into four groups(n=8):the normal-diet group(ND),the normal-diet group treated with melatonin(10 mg·kg^(-1))(ND+MLT),the high-fat-diet group(HFD),and the high-fat-diet group treated with melatonin(HFD+MLT).After 12 weeks,the expression levels of pyroptosis related genes including NLRP3,ASC,cleaved-caspase 1,GSDMD-N,IL-1β and IL-18 were examined in aortic endothelium by Western blotting,qRT-PCR and immunofluorescent staining.Besides,levels of MEG3 and miR-223 were also tested by qRT-PCR.The interaction between MEG3 and miR-223 was detected by luciferase assay.For in vitro study,human aortic endothelial cells(HAECs) were transiently transfected with miR-223 mimic,miR-223 inhibitor(AMO-223),MEG3-overexpressing plasmid or negative controls.After 6 h of transfection,the medium was replaced by fresh medium with or without ox-LDL(25 μg·mL-1) for 24 h and then treated with or without melatonin(10 μmol·L^(-1)) for 48 h.Cell pyroptosis was evaluated by Hoechst 33342/PI staining and differentially expressed pyroptosis related genes.RESULTS Melatonin markedly reduced the atherosclerotic plaque in aorta of ApoE-/-mice.Meanwhile,melatonin also attenuated the expression NLRP3,ASC,cleaved-caspase1,NF-κB/GSDMD,GSDMD-N termini,IL-1β,and IL-18 in aortic endo.thelium.Consistent anti-pyroptotic effects were also observed in ox-LDL-treated HAECs.We found that lncRNAMEG3 enhanced pyroptosis in HAECs.Moreover,MEG3 acted as an endogenous sponge by sequence complementarity to suppress the function of miR-223 and to increase NLRP3 expression and enhance endothelial cell pyroptosis.Furthermore,knockdown of miR-223 blocked the anti-pyroptotic actions of melatonin in ox-LDL-treated HAECs.CONCLUSION Melatonin prevents endothelial cell pyroptosis via MEG3/miR-223/NLRP3 axis in atherosclerosis and therefore melatonin replacement might be considered a new strat展开更多
Background：Pyroptosis is the term for caspase-l-dependent cell death associated with pro-inflammatory cytokines.The role of alveolar macrophage （AM） pyroptosis in the pathogenesis of the acute lung injury and acute...Background：Pyroptosis is the term for caspase-l-dependent cell death associated with pro-inflammatory cytokines.The role of alveolar macrophage （AM） pyroptosis in the pathogenesis of the acute lung injury and acute respiratory distress syndrome （ALI/ARDS） remains unclear.Methods：C57BL/6 wild-type mice were assigned to sham,lipopolysaccharide （LPS） ＋ vehicle,LPS ＋ acetyl-tyrosyl-valyl-alanyl-aspartyl-chloromethylketone （Ac-YVAD-CMK） and LPS ＋ Z-Asp-Glu-Val-Asp-fluoromethylketone groups.Mice were given intraperitoneal （IP） injections of LPS.Drugs were IP injected 1 h before LPS administration.Mice were sacrificed 16 h after LPS administration,and AMs were isolated.Western blot analysis for active caspase-1 and cleaved caspase-3,evaluation of lung injury and a cytokine release analysis were performed.AMs were treated with LPS and adenosine triphosphate （ATP）;caspase-l-dependent cell death was evaluated using flow cytometry;the apoptosis-associated speck-like protein containing a caspase recruitment domain （ASC） pyroptosomes were examined by immunofluorescence.Results：The expression of activated caspase-1 in AMs was enhanced following LPS challenge compared with the sham group.In the ex vivo study,the caspase-1/propidium iodide-positive cells,caspase-1 specks and ASC pyroptosomes were up-regulated in AMs following LPS/ATP stimulation.The specific caspase-1 inhibitor Ac-YVAD-CMK inhibited the activation of caspase-1 and pyroptotic cell death.Ac-YVAD-CMK also reduced the lung injury,pulmonary edema and total protein in bronchoalveolar lavage fluid （BALF）.In addition,Ac-YVAD-CMK significantly inhibited interleukin-β （IL-lβ） release both in serum and BALF and reduced the levels of IL-18,tumor necrosis factor-α （TNF-α）,High Mobility Group Box 1 （HMGB1） in BALF during LPS-induced ALI/ARDS.Conclusions：This study reported AM pyroptosis during LPS-induced ALI/ARDS in mice and has demonstrated that Ac-YVAD-CMK can prevent AM-induced pyroptosis and lung injury.These 展开更多
Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other gasdermin family proteins, ...Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other gasdermin family proteins, does not induce cell death. Here, we show that GSDMB is highly expressed in the leukocytes of septic shock patients, which is associated with increased release of the gasdermin D (GSDMD) N-terminus. GSDMB expression and the accumulation of the N-terminal fragment of GSDMD are induced by the activation of the non-canonical pyroptosis pathway in a human monocyte cell line. The downregulation of GSDMB alleviates the cleavage of GSDMD and cell death. Consistently, the overexpression of GSDMB promotes GSDMD cleavage, accompanied by increased LDH release. We further found that GSDMB promotes caspase-4 activity, which is required for the cleavage of GSDMD in non-canonical pyroptosis, by directly binding to the CARD domain of caspase-4. Our study reveals a GSDMB-mediated novel regulatory mechanism for non-canonical pyroptosis and suggests a potential new strategy for the treatment of inflammatory diseases.展开更多
基金This work was supported by the Fundamental Research Funds for the Central Universities(WK2070000191,WK9110000037)the fellowship of China National Postdoctoral Program for Innovative Talents(BX20200325)the Natural Science Foundation of Anhui province(1808085QH244).
文摘The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3,adapter protein ASC,and inflammatory protease caspase-1 that responds to microbial infection,endogenous danger signals,and environmental stimuli.The assembled NLRP3 inflammasome can activate the protease caspase‐1 to induce gasdermin D-dependent pyroptosis and facilitate the release of IL-1β and IL-18,which contribute to innate immune defense and homeostatic maintenance.However,aberrant activation of the NLRP3 inflammasome is associated with the pathogenesis of various inflammatory diseases,such as diabetes,cancer,and Alzheimer’s disease.Recent studies have revealed that NLRP3 inflammasome activation contributes to not only pyroptosis but also other types of cell death,including apoptosis,necroptosis,and ferroptosis.In addition,various effectors of cell death have been reported to regulate NLRP3 inflammasome activation,suggesting that cell death is closely related to NLRP3 inflammasome activation.In this review,we summarize the inextricable link between NLRP3 inflammasome activation and cell death and discuss potential therapeutics that target cell death effectors in NLRP3 inflammasome-associated diseases.
基金B.S.F.is supported by grants from the European Research Council(PLAT-IL-1,714175)B.S.F.and E.L.are further supported by grants from the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)(SFBTRR57)the DFG Germany’s Excellence Strategy-EXC 2151-390873048.
文摘Cell death is a fundamental physiological process in all living organisms.Its roles extend from embryonic development,organ maintenance,and aging to the coordination of immune responses and autoimmunity.In recent years,our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially.Different modalities of what has become known as‘programmed cell death’have been described,and some key players in these processes have been identified.We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death.These studies have highlighted the complex mechanisms tipping the balance between different cell fates.Here,we summarize the latest discoveries in the three most well understood modalities of cell death,namely,apoptosis,necroptosis,and pyroptosis,highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.
基金supported by a grant from the National Institute of General Medical Sciences(P20 GM103429,USA)grants from National Heart,Lung and Blood Institute(HL153876,USA)National Eye Institute(EY030621,USA)
文摘Pyroptosis is the process of inflammatory cell death.The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection.Excessive pyroptosis,however,leads to several inflammatory diseases,including sepsis and autoimmune disorders.Pyroptosis can be canonical or noncanonical.Upon microbe infection,the canonical pathway responds to pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs),while the noncanonical pathway responds to intracellular lipopolysaccharides(LPS) of Gram-negative bacteria.The last step of pyroptosis requires the cleavage of gasdermin D(GsdmD) at D275(numbering after human GSDMD) into N-and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11(caspase 4/5 in humans,caspase 11 in mice) in the noncanonical pathway.Upon cleavage,the N-terminus of GsdmD(GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1β and IL-18 and disturbs the regulation of ions and water,eventually resulting in strong inflammation and cell death.Since GsdmD is the effector of pyroptosis,promising inhibitors of GsdmD have been developed for inflammatory diseases.This review will focus on the roles of GsdmD during pyroptosis and in diseases.
基金supported by National Natural Science Foundation of China(8157039981270042)
文摘OBJECTIVE To investigate the anti-pyroptotic effects of melatonin in atherosclerotic endothelium and to elucidate the potential mechanisms.METHODS ApoE-/-mice were randomly divid.ed into four groups(n=8):the normal-diet group(ND),the normal-diet group treated with melatonin(10 mg·kg^(-1))(ND+MLT),the high-fat-diet group(HFD),and the high-fat-diet group treated with melatonin(HFD+MLT).After 12 weeks,the expression levels of pyroptosis related genes including NLRP3,ASC,cleaved-caspase 1,GSDMD-N,IL-1β and IL-18 were examined in aortic endothelium by Western blotting,qRT-PCR and immunofluorescent staining.Besides,levels of MEG3 and miR-223 were also tested by qRT-PCR.The interaction between MEG3 and miR-223 was detected by luciferase assay.For in vitro study,human aortic endothelial cells(HAECs) were transiently transfected with miR-223 mimic,miR-223 inhibitor(AMO-223),MEG3-overexpressing plasmid or negative controls.After 6 h of transfection,the medium was replaced by fresh medium with or without ox-LDL(25 μg·mL-1) for 24 h and then treated with or without melatonin(10 μmol·L^(-1)) for 48 h.Cell pyroptosis was evaluated by Hoechst 33342/PI staining and differentially expressed pyroptosis related genes.RESULTS Melatonin markedly reduced the atherosclerotic plaque in aorta of ApoE-/-mice.Meanwhile,melatonin also attenuated the expression NLRP3,ASC,cleaved-caspase1,NF-κB/GSDMD,GSDMD-N termini,IL-1β,and IL-18 in aortic endo.thelium.Consistent anti-pyroptotic effects were also observed in ox-LDL-treated HAECs.We found that lncRNAMEG3 enhanced pyroptosis in HAECs.Moreover,MEG3 acted as an endogenous sponge by sequence complementarity to suppress the function of miR-223 and to increase NLRP3 expression and enhance endothelial cell pyroptosis.Furthermore,knockdown of miR-223 blocked the anti-pyroptotic actions of melatonin in ox-LDL-treated HAECs.CONCLUSION Melatonin prevents endothelial cell pyroptosis via MEG3/miR-223/NLRP3 axis in atherosclerosis and therefore melatonin replacement might be considered a new strat
基金The author thanks the National Natural Science Foundation of China （No. 81470266）.
文摘Background：Pyroptosis is the term for caspase-l-dependent cell death associated with pro-inflammatory cytokines.The role of alveolar macrophage （AM） pyroptosis in the pathogenesis of the acute lung injury and acute respiratory distress syndrome （ALI/ARDS） remains unclear.Methods：C57BL/6 wild-type mice were assigned to sham,lipopolysaccharide （LPS） ＋ vehicle,LPS ＋ acetyl-tyrosyl-valyl-alanyl-aspartyl-chloromethylketone （Ac-YVAD-CMK） and LPS ＋ Z-Asp-Glu-Val-Asp-fluoromethylketone groups.Mice were given intraperitoneal （IP） injections of LPS.Drugs were IP injected 1 h before LPS administration.Mice were sacrificed 16 h after LPS administration,and AMs were isolated.Western blot analysis for active caspase-1 and cleaved caspase-3,evaluation of lung injury and a cytokine release analysis were performed.AMs were treated with LPS and adenosine triphosphate （ATP）;caspase-l-dependent cell death was evaluated using flow cytometry;the apoptosis-associated speck-like protein containing a caspase recruitment domain （ASC） pyroptosomes were examined by immunofluorescence.Results：The expression of activated caspase-1 in AMs was enhanced following LPS challenge compared with the sham group.In the ex vivo study,the caspase-1/propidium iodide-positive cells,caspase-1 specks and ASC pyroptosomes were up-regulated in AMs following LPS/ATP stimulation.The specific caspase-1 inhibitor Ac-YVAD-CMK inhibited the activation of caspase-1 and pyroptotic cell death.Ac-YVAD-CMK also reduced the lung injury,pulmonary edema and total protein in bronchoalveolar lavage fluid （BALF）.In addition,Ac-YVAD-CMK significantly inhibited interleukin-β （IL-lβ） release both in serum and BALF and reduced the levels of IL-18,tumor necrosis factor-α （TNF-α）,High Mobility Group Box 1 （HMGB1） in BALF during LPS-induced ALI/ARDS.Conclusions：This study reported AM pyroptosis during LPS-induced ALI/ARDS in mice and has demonstrated that Ac-YVAD-CMK can prevent AM-induced pyroptosis and lung injury.These
基金Research from the corresponding author’s laboratory was supported by grants from National Institutes of Health,USA(No.R01GM117628,R01GM122406,and R01DK123826)Merit Review Award(No.I01BX001690)from US Department of Veterans Affairs.
基金the Ministry of Science and Technology of China (2015BAI08B02 and 2014BAI02B01)the National Natural Science Foundation of China (31772550, 31301217,81772052, and 31500944)the Natural Science Foundation of Jiangsu Province (BK20181260).
文摘Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other gasdermin family proteins, does not induce cell death. Here, we show that GSDMB is highly expressed in the leukocytes of septic shock patients, which is associated with increased release of the gasdermin D (GSDMD) N-terminus. GSDMB expression and the accumulation of the N-terminal fragment of GSDMD are induced by the activation of the non-canonical pyroptosis pathway in a human monocyte cell line. The downregulation of GSDMB alleviates the cleavage of GSDMD and cell death. Consistently, the overexpression of GSDMB promotes GSDMD cleavage, accompanied by increased LDH release. We further found that GSDMB promotes caspase-4 activity, which is required for the cleavage of GSDMD in non-canonical pyroptosis, by directly binding to the CARD domain of caspase-4. Our study reveals a GSDMB-mediated novel regulatory mechanism for non-canonical pyroptosis and suggests a potential new strategy for the treatment of inflammatory diseases.
