Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells ...Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.展开更多
Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterize...Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood-brain barrier,which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells,oligodendrocytes(Oh et al.,2018).There is a prevalence sexual with a ratio of three times more affected women than men.展开更多
目的从动物和细胞两个层面探讨趋化因子配体7[chemokine(C-X-C motif)ligand 7,CXCL7]/趋化因子受体2(CXCR2)轴在肥胖相关认知功能障碍中的作用机制。方法高脂饮食诱导的肥胖模型(diet-induced obesity,DIO),采用新物体识别实验检测认...目的从动物和细胞两个层面探讨趋化因子配体7[chemokine(C-X-C motif)ligand 7,CXCL7]/趋化因子受体2(CXCR2)轴在肥胖相关认知功能障碍中的作用机制。方法高脂饮食诱导的肥胖模型(diet-induced obesity,DIO),采用新物体识别实验检测认知水平;免疫荧光染色法观察海马小胶质细胞、星形胶质细胞的活化水平以及小鼠突触后密度蛋白95(postsynaptic density protein 95,PSD95)的含量。采用ELISA法测定海马组织CXCL7的含量;高尔基染色法测定海马神经元树突棘密度。其次,分别使用重组小鼠CXCL7和干扰CXCR2表达的si-RNA处理HT22小鼠海马神经元细胞系。用细胞免疫荧光染色法观察HT22细胞的CXCL7和PSD95的表达水平。结果与Ctrl组小鼠比较,DIO组小鼠在新物体识别实验中的辨别指数明显降低;伴有海马小胶质细胞、星形胶质细胞的活化水平明显升高,PSD95的含量减少,神经元的树突棘密度降低,CXCL7的含量明显升高。与DIO组小鼠相比,AWL组小鼠在新物体识别实验中的辨别指数明显升高。与Ctrl组细胞比,Ctrl+CXCL7组的PSD95水平降低;与Ctrl+CXCL7组细胞比,si-CXCR2+CXCL7组的PSD95水平升高。结论高脂饮食诱导肥胖小鼠的中枢神经炎症,进而引起认知功能障碍,可能是与CXCL7/CXCR2轴介导的突触可塑性改变有关。展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271397(to MG),82001293(to MG),82171355(to RX),81971295(to RX),and 81671189(to RX)。
文摘Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.
基金supported by a grant from the French Multiple Sclerosis Society(ARSEP,Grant Number:R20163LL)(to AMG)。
文摘Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood-brain barrier,which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells,oligodendrocytes(Oh et al.,2018).There is a prevalence sexual with a ratio of three times more affected women than men.
文摘目的从动物和细胞两个层面探讨趋化因子配体7[chemokine(C-X-C motif)ligand 7,CXCL7]/趋化因子受体2(CXCR2)轴在肥胖相关认知功能障碍中的作用机制。方法高脂饮食诱导的肥胖模型(diet-induced obesity,DIO),采用新物体识别实验检测认知水平;免疫荧光染色法观察海马小胶质细胞、星形胶质细胞的活化水平以及小鼠突触后密度蛋白95(postsynaptic density protein 95,PSD95)的含量。采用ELISA法测定海马组织CXCL7的含量;高尔基染色法测定海马神经元树突棘密度。其次,分别使用重组小鼠CXCL7和干扰CXCR2表达的si-RNA处理HT22小鼠海马神经元细胞系。用细胞免疫荧光染色法观察HT22细胞的CXCL7和PSD95的表达水平。结果与Ctrl组小鼠比较,DIO组小鼠在新物体识别实验中的辨别指数明显降低;伴有海马小胶质细胞、星形胶质细胞的活化水平明显升高,PSD95的含量减少,神经元的树突棘密度降低,CXCL7的含量明显升高。与DIO组小鼠相比,AWL组小鼠在新物体识别实验中的辨别指数明显升高。与Ctrl组细胞比,Ctrl+CXCL7组的PSD95水平降低;与Ctrl+CXCL7组细胞比,si-CXCR2+CXCL7组的PSD95水平升高。结论高脂饮食诱导肥胖小鼠的中枢神经炎症,进而引起认知功能障碍,可能是与CXCL7/CXCR2轴介导的突触可塑性改变有关。
