Background:Alzheimer's disease(AD)is a progressive neurodegenerative disease with no effective therapies.It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD.Wel...Background:Alzheimer's disease(AD)is a progressive neurodegenerative disease with no effective therapies.It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD.Well-balanced neuronal-microglial interactions are essential for brain functions.However,determining the role of microglia—the primary immune cells in the brain—in neuroinflammation in AD and the associated molecular basis has been challenging.Methods:Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed.The mechanism for microglial inflammation was investigated.IL6 and TNF-α were found to be significantly increased in the AD stage.Results:Our analysis revealed that microglia were extensively activated in AD cerebra,releasing sufficient amounts of cytokines to impair the neural stem cells(NSCs)function.Moreover,the ApoD-induced NLRC4 inflammasome was activated in microglia,which gave rise to the proinflammatory phenotype.Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis.These findings demonstrate the critical role of ApoD in microglial inflammasome activation,and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation.Conclusion:Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.展开更多
Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have...Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.展开更多
Streptococcus mutans(S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin(IL...Streptococcus mutans(S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin(IL)-1β, a proinflammatory cytokine, is related to the host defences against pathogens, and its synthesis, maturation, and secretion are tightly regulated by the activation of the inflammasome, an inflammatory signalling complex. This study examined the signalling mechanism of IL-1β secretion and the inflammasome pathway induced by S. mutans to explain the molecular mechanism through which systemic infection by oral streptococci can occur. After infection of THP-1 cells with S. mutans, the expression of inflammasome components was detected using various methods. S. mutans induced IL-1β secretion via caspase-1 activation, and S. mutans-induced IL-1β secretion required absent in melanoma(AIM2), NLR family pyrin domain-containing 3(NLRP3) and NLR family CARD domain-containing 4(NLRC4)inflammasome activation. In particular, the S. mutans-induced NLRP3 inflammasome was mediated by adenosine triphosphate(ATP) release, potassium depletion and lysosomal damage. Our study provides novel insight into the innate immune response against S. mutans infection.展开更多
目的探讨炎症小体NLR家族含CARD结构蛋白4(NLR family CARD domain-containing protein 4,NLRC4)的表达与急性脑梗死(acute cerebral infarction,ACI)之间的关系。方法选取2019年5月—2020年8月就诊于徐州医科大学附属淮海医院神经内科...目的探讨炎症小体NLR家族含CARD结构蛋白4(NLR family CARD domain-containing protein 4,NLRC4)的表达与急性脑梗死(acute cerebral infarction,ACI)之间的关系。方法选取2019年5月—2020年8月就诊于徐州医科大学附属淮海医院神经内科的39例ACI患者作为研究组,另选取同期于我院进行健康体检的40例患者作为对照组。酶联免疫吸附法检测患者及大鼠外周血中NLRC4、白介素-1β(IL-1β)及白介素-18(IL-18)的表达水平。通过阻断大鼠大脑中动脉血流24 h构建大鼠ACI动物模型,使用蛋白免疫印迹实验、组织切片免疫荧光染色实验评估缺血损伤对大鼠脑组织中NLRC4表达的影响。结果与对照组相比,研究组患者在年龄、体质量指数、性别构成、糖尿病以及吸烟情况方面差异无统计学意义(P>0.05),而高血压患者比例增高(P<0.05);血生化检查项目中,研究组患者外周血中C-反应蛋白水平较对照组显著升高(P<0.05),而高密度脂蛋白水平低于对照组(P<0.05);研究组患者外周血中NLRC4、IL-1β的表达较对照组显著升高(P<0.05)。蛋白免疫印迹实验结果显示NLRC4在缺血损伤大鼠脑组织中表达上调,差异有统计学意义(P<0.05);组织切片免疫荧光染色结果显示NLRC4在缺血损伤的神经元细胞中表达升高;ELISA结果显示NLRC4、IL-1β及IL-18在ACI大鼠外周血中的表达水平较对照组显著升高(P<0.05)。结论NLRC4及其介导的炎症小体信号在ACI脑组织中显著上调,具有作为新型ACI治疗靶点的潜力。展开更多
基金supported by the Guiding Science and Technology Development Grant in the Social Sector of Luoyang(2101083A)。
文摘Background:Alzheimer's disease(AD)is a progressive neurodegenerative disease with no effective therapies.It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD.Well-balanced neuronal-microglial interactions are essential for brain functions.However,determining the role of microglia—the primary immune cells in the brain—in neuroinflammation in AD and the associated molecular basis has been challenging.Methods:Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed.The mechanism for microglial inflammation was investigated.IL6 and TNF-α were found to be significantly increased in the AD stage.Results:Our analysis revealed that microglia were extensively activated in AD cerebra,releasing sufficient amounts of cytokines to impair the neural stem cells(NSCs)function.Moreover,the ApoD-induced NLRC4 inflammasome was activated in microglia,which gave rise to the proinflammatory phenotype.Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis.These findings demonstrate the critical role of ApoD in microglial inflammasome activation,and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation.Conclusion:Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.
基金supported the National Natural Science Foundation of China,No.81974178(to CD).
文摘Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.
基金A National Research Foundation of Korea (NRF) grant funded by the government of South Korea (MEST no. 2012R1A2A2A01015470) supported this research
文摘Streptococcus mutans(S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin(IL)-1β, a proinflammatory cytokine, is related to the host defences against pathogens, and its synthesis, maturation, and secretion are tightly regulated by the activation of the inflammasome, an inflammatory signalling complex. This study examined the signalling mechanism of IL-1β secretion and the inflammasome pathway induced by S. mutans to explain the molecular mechanism through which systemic infection by oral streptococci can occur. After infection of THP-1 cells with S. mutans, the expression of inflammasome components was detected using various methods. S. mutans induced IL-1β secretion via caspase-1 activation, and S. mutans-induced IL-1β secretion required absent in melanoma(AIM2), NLR family pyrin domain-containing 3(NLRP3) and NLR family CARD domain-containing 4(NLRC4)inflammasome activation. In particular, the S. mutans-induced NLRP3 inflammasome was mediated by adenosine triphosphate(ATP) release, potassium depletion and lysosomal damage. Our study provides novel insight into the innate immune response against S. mutans infection.
文摘目的探讨炎症小体NLR家族含CARD结构蛋白4(NLR family CARD domain-containing protein 4,NLRC4)的表达与急性脑梗死(acute cerebral infarction,ACI)之间的关系。方法选取2019年5月—2020年8月就诊于徐州医科大学附属淮海医院神经内科的39例ACI患者作为研究组,另选取同期于我院进行健康体检的40例患者作为对照组。酶联免疫吸附法检测患者及大鼠外周血中NLRC4、白介素-1β(IL-1β)及白介素-18(IL-18)的表达水平。通过阻断大鼠大脑中动脉血流24 h构建大鼠ACI动物模型,使用蛋白免疫印迹实验、组织切片免疫荧光染色实验评估缺血损伤对大鼠脑组织中NLRC4表达的影响。结果与对照组相比,研究组患者在年龄、体质量指数、性别构成、糖尿病以及吸烟情况方面差异无统计学意义(P>0.05),而高血压患者比例增高(P<0.05);血生化检查项目中,研究组患者外周血中C-反应蛋白水平较对照组显著升高(P<0.05),而高密度脂蛋白水平低于对照组(P<0.05);研究组患者外周血中NLRC4、IL-1β的表达较对照组显著升高(P<0.05)。蛋白免疫印迹实验结果显示NLRC4在缺血损伤大鼠脑组织中表达上调,差异有统计学意义(P<0.05);组织切片免疫荧光染色结果显示NLRC4在缺血损伤的神经元细胞中表达升高;ELISA结果显示NLRC4、IL-1β及IL-18在ACI大鼠外周血中的表达水平较对照组显著升高(P<0.05)。结论NLRC4及其介导的炎症小体信号在ACI脑组织中显著上调,具有作为新型ACI治疗靶点的潜力。
