We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repet...We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.展开更多
Although the functional parameters of micro RNAs(mi RNAs)have been explored to some extent,the roles of these molecules in coronavirus infection and the regulatory mechanism of mi RNAs in virus infection are still unc...Although the functional parameters of micro RNAs(mi RNAs)have been explored to some extent,the roles of these molecules in coronavirus infection and the regulatory mechanism of mi RNAs in virus infection are still unclear.Transmissible gastroenteritis virus(TGEV)is an enteropathgenic coronavirus and causes high morbidity and mortality in suckling piglets.Here,we demonstrated that microRNA-27b-3p(miR-27b-3p)suppressed TGEV replication by directly targeting porcine suppressor of cytokine signaling 6(SOCS6),while TGEV infection downregulated miR-27b-3p expression in swine testicular(ST)cells and in piglets.Mechanistically,the decrease of miR-27b-3p expression during TGEV infection was mediated by the activated inositolrequiring enzyme 1(IRE1)pathway of the endoplasmic reticulum(ER)stress.Further studies showed that when ER stress was induced by TGEV,IRE1 acted as an RNase activated by autophosphorylation and unconventionally spliced m RNA encoding a potent transcription factor,X-box-binding protein 1(Xbp1s).Xbp1s inhibited the transcription of miR-27 and ultimately reduced the production of miR-27b-3p.Therefore,our findings indicate that TGEV inhibits the expression of an anti-coronavirus micro RNA through the IRE1 pathway and suggest a novel way in which coronavirus regulates the host cell response to infection.展开更多
Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1...Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.展开更多
基金supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBSS00047(to PL)the National Natural Science Foundation of China,Nos.82072166(to PL),82071394(to XG)+4 种基金Science and Technology Planning Project of Tianjin,No.20YFZCSY00030(to PL)Science and Technology Project of Tianjin Municipal Health Commission,No.TJWJ2021QN005(to XG)Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-006ATianjin Municipal Education Commission Scientific Research Program Project,No.2020KJ164(to JZ)China Postdoctoral Science Foundation,No.2022M712392(to ZY).
文摘We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.
基金supported by the Heilongjiang Postdoctoral fund(LBH-Z18207)the National Natural Science Foundation of China(31802198)+2 种基金the Fundamental Research Funds for the Provincial Universities(2018-KYYWF-0553)the National Key Research and Development Program of China(2017YFC0908001)the Spark Research Fund from the Fourth Affiliated Hospital of Harbin Medical University(HYDSYXH201914)。
文摘Although the functional parameters of micro RNAs(mi RNAs)have been explored to some extent,the roles of these molecules in coronavirus infection and the regulatory mechanism of mi RNAs in virus infection are still unclear.Transmissible gastroenteritis virus(TGEV)is an enteropathgenic coronavirus and causes high morbidity and mortality in suckling piglets.Here,we demonstrated that microRNA-27b-3p(miR-27b-3p)suppressed TGEV replication by directly targeting porcine suppressor of cytokine signaling 6(SOCS6),while TGEV infection downregulated miR-27b-3p expression in swine testicular(ST)cells and in piglets.Mechanistically,the decrease of miR-27b-3p expression during TGEV infection was mediated by the activated inositolrequiring enzyme 1(IRE1)pathway of the endoplasmic reticulum(ER)stress.Further studies showed that when ER stress was induced by TGEV,IRE1 acted as an RNase activated by autophosphorylation and unconventionally spliced m RNA encoding a potent transcription factor,X-box-binding protein 1(Xbp1s).Xbp1s inhibited the transcription of miR-27 and ultimately reduced the production of miR-27b-3p.Therefore,our findings indicate that TGEV inhibits the expression of an anti-coronavirus micro RNA through the IRE1 pathway and suggest a novel way in which coronavirus regulates the host cell response to infection.
基金This work was supported by USA National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)R01 DK093807.
文摘Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.
