African swine fever virus(ASFV)is an important pathogen causing acute infectious disease in domestic pigs and wild boars that seriously endangers the global swine industry.As ASFV is structurally complex and encodes a...African swine fever virus(ASFV)is an important pathogen causing acute infectious disease in domestic pigs and wild boars that seriously endangers the global swine industry.As ASFV is structurally complex and encodes a large number of functional proteins,no effective vaccine has been developed to date.Thus,dissecting the mechanisms of immune escape induced by ASFV proteins is crucial.A previous study showed that the ASFV-encoded protein is an important factor in host immunity.In this study,we identified a negative regulator,MGF505-3R,that significantly downregulated cGAS/STING-and poly(dG:dC)-mediated IFN-βand interferon stimulation response element(ISRE)reporter activity and suppressed IFNB1 and IFIT2 mRNA levels.In addition,TBK1,IRF3 and IκBαphosphorylation levels were also inhibited.Mechanistically,MGF505-3R interacted with cGAS/TBK1/IRF3 and targeted TBK1 for degradation,thereby disrupting the cGAS-STING-mediated IFN-βsignaling pathway,which appears to be highly correlated with autophagy.Knockdown MGF505-3R expression enhanced IFN-βand IL-1βproduction.Taken together,our study revealed a negative regulatory mechanism involving the MGF505-3R-cGAS-STING axis and provided insights into an evasion strategy employed by ASFV that involves autophagy and innate signaling pathways.展开更多
Background:Recurrent implantation failure(RIF)is a difficult problem with a multifaceted cause.Recent studies have demonstrated that stimulator of interferon genes-induced immune-related genes(STIRGs)are associated wi...Background:Recurrent implantation failure(RIF)is a difficult problem with a multifaceted cause.Recent studies have demonstrated that stimulator of interferon genes-induced immune-related genes(STIRGs)are associated with immune disorders that may affect the endometrial immune micro-environment.However,the effect of STRIGs on RIF remains unknown.Methods:Training(GSE111974)and validation(GSE106602)cohorts were acquired from the Gene Expression Omnibus database.STIRGs were extracted from the Molecular Signatures Database and relevant studies.Consensus clustering analysis was used to identify RIF molecular subtypes.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment and immune infiltration analyses were performed between RIF subtypes.Drug-related potential therapeutic target genes were discovered.Results:Two distinct molecular subtypes were discovered in both the training and validation groups according to STIRGs.In subtype C2,there was a notable decrease in the presence of different types of immune cells,such as natural killer cells and macrophages.Furthermore,the examination of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes indicated a decrease in numerous immune-related biological processes within subtype C2.Finally,nine hub genes(CXCR4,POU5F1,PPARG,TLR2,EGFR,CSF1,BCL2A1,BTK,and SRGN)were identified as potential therapeutic targets for RIF.Conclusion:Based on STIRGs,we identified a new molecular subtype with significantly reduced immune infiltration in RIF.Nine genes might be potential therapeutic targets for RIF.展开更多
Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanost...Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanostimulator(CMS)is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening,which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently.On one hand,glutathione(GSH)depletion and reactive oxygen species(ROS)generation can be achieved due to the mixed valence state of Mn in CMS.On the other hand,as an exotic Ca2+supplier,CMS causes mitochondrial Ca2+overload,which further amplifies the oxidative stress.Significantly,tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4(GPX4)and accumulation of lipid peroxidation(LPO).More impressively,CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway,which promotes polarization of tumor-associated macrophages(TAMs)and activation of dendritic cells(DCs)for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes(CTLs)into tumor tissues.Taken together,this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity,offering a new perspective for effective tumor immunotherapy of TNBC.展开更多
基金supported by the National Natural Science Foundation of China(31941018,32072888,U21A20261)China Agriculture Research System of MOF and MARA(CARS-35)+1 种基金Science and Technology Development Program of Jilin Province(YDZJ202102CXJD029,20190301042NY,20200402041NC)Science and Technology Development Program of Changchun City(21ZY42).
文摘African swine fever virus(ASFV)is an important pathogen causing acute infectious disease in domestic pigs and wild boars that seriously endangers the global swine industry.As ASFV is structurally complex and encodes a large number of functional proteins,no effective vaccine has been developed to date.Thus,dissecting the mechanisms of immune escape induced by ASFV proteins is crucial.A previous study showed that the ASFV-encoded protein is an important factor in host immunity.In this study,we identified a negative regulator,MGF505-3R,that significantly downregulated cGAS/STING-and poly(dG:dC)-mediated IFN-βand interferon stimulation response element(ISRE)reporter activity and suppressed IFNB1 and IFIT2 mRNA levels.In addition,TBK1,IRF3 and IκBαphosphorylation levels were also inhibited.Mechanistically,MGF505-3R interacted with cGAS/TBK1/IRF3 and targeted TBK1 for degradation,thereby disrupting the cGAS-STING-mediated IFN-βsignaling pathway,which appears to be highly correlated with autophagy.Knockdown MGF505-3R expression enhanced IFN-βand IL-1βproduction.Taken together,our study revealed a negative regulatory mechanism involving the MGF505-3R-cGAS-STING axis and provided insights into an evasion strategy employed by ASFV that involves autophagy and innate signaling pathways.
文摘Background:Recurrent implantation failure(RIF)is a difficult problem with a multifaceted cause.Recent studies have demonstrated that stimulator of interferon genes-induced immune-related genes(STIRGs)are associated with immune disorders that may affect the endometrial immune micro-environment.However,the effect of STRIGs on RIF remains unknown.Methods:Training(GSE111974)and validation(GSE106602)cohorts were acquired from the Gene Expression Omnibus database.STIRGs were extracted from the Molecular Signatures Database and relevant studies.Consensus clustering analysis was used to identify RIF molecular subtypes.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment and immune infiltration analyses were performed between RIF subtypes.Drug-related potential therapeutic target genes were discovered.Results:Two distinct molecular subtypes were discovered in both the training and validation groups according to STIRGs.In subtype C2,there was a notable decrease in the presence of different types of immune cells,such as natural killer cells and macrophages.Furthermore,the examination of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes indicated a decrease in numerous immune-related biological processes within subtype C2.Finally,nine hub genes(CXCR4,POU5F1,PPARG,TLR2,EGFR,CSF1,BCL2A1,BTK,and SRGN)were identified as potential therapeutic targets for RIF.Conclusion:Based on STIRGs,we identified a new molecular subtype with significantly reduced immune infiltration in RIF.Nine genes might be potential therapeutic targets for RIF.
基金supported by the National Key Research and Development Program of China(Grant No.2021YFB3801000)the National Natural Science Foundation of China(Grant No.32030061)+3 种基金the Basic Research Program of Shanghai Municipal Government(Grant No.21JC1406000)the Shanghai Sailing Program(Grant No.21YF1454200)Shanghai International Cooperation Project(Grant No.23490712900)All the animal experiments were performed with the approval of the Tongji University Experimental Animal Center,and the animal biomedical research authorization number is TJLAC-020-228.
文摘Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanostimulator(CMS)is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening,which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently.On one hand,glutathione(GSH)depletion and reactive oxygen species(ROS)generation can be achieved due to the mixed valence state of Mn in CMS.On the other hand,as an exotic Ca2+supplier,CMS causes mitochondrial Ca2+overload,which further amplifies the oxidative stress.Significantly,tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4(GPX4)and accumulation of lipid peroxidation(LPO).More impressively,CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway,which promotes polarization of tumor-associated macrophages(TAMs)and activation of dendritic cells(DCs)for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes(CTLs)into tumor tissues.Taken together,this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity,offering a new perspective for effective tumor immunotherapy of TNBC.
