Interleukin 17A(IL-17A)was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications.However,the role of IL-17A in diabetic encephalopathy remains poorly understood.In this...Interleukin 17A(IL-17A)was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications.However,the role of IL-17A in diabetic encephalopathy remains poorly understood.In this study,we established a mouse model of diabetic encephalopathy that was deficient in IL-17A by crossing Il17a-/-mice with spontaneously diabetic Ins2^(Akita)(Akita)mice.Blood glucose levels and body weights were monitored from 2-32 weeks of age.When mice were 32 weeks of age,behavioral tests were performed,including a novel object recognition test for assessing short-term memory and learning and a Morris water maze test for evaluating hippocampus-dependent spatial learning and memory.IL-17A levels in the serum,cerebrospinal fluid,and hippocampus were detected with enzyme-linked immunosorbent assays and real-time quantitative polymerase chain reaction.Moreover,proteins related to cognitive dysfunction(amyloid precursor protein,β-amyloid cleavage enzyme 1,p-tau,and tau),apoptosis(caspase-3 and-9),inflammation(inducible nitric oxide synthase and cyclooxygenase 2),and occludin were detected by western blot assays.Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin-1β,and interferon-γin serum and hippocampal tissues were measured by enzyme-linked immunosorbent assays.Microglial activation and hippocampal neuronal apoptosis were detected by immunofluorescent staining.Compared with that in wild-type mice,mice with diabetic encephalopathy had higher IL-17A levels in the serum,cerebrospinal fluid,and hippocampus;downregulation of occludin expression;lower cognitive ability;greater loss of hippocampal neurons;increased microglial activation;and higher expression of inflammatory factors in the serum and hippocampus.IL-17A knockout attenuated the abovementioned changes in mice with diabetic encephalopathy.These findings suggest that IL-17A participates in the pathological process of diabetic encephalopathy.Furthermore,IL-17A deficiency reduces diabetic encephalopathy-mediated neuroinflammation and cognitive defects.These results highlight a role for IL-17A as a mediator of diabetic encephalopathy and potential target for the treatment of cognitive impairment induced by diabetic encephalopathy.展开更多
Summary:Interleukin 17A(IL 17A)is reported to be involved in many inflammatory processes,but its role in aortic valve diseases remains unknown.We examined the role of IL17A based on an ApoE^-/-mouse model with strateg...Summary:Interleukin 17A(IL 17A)is reported to be involved in many inflammatory processes,but its role in aortic valve diseases remains unknown.We examined the role of IL17A based on an ApoE^-/-mouse model with strategies as fed with high-fat diet or treated with ILI7A monoclonal antibody(mAb).12 weeks of high-fat diet feeding can elevate cytokines secretion,inflammatory cells infiltration and myofibroblastic transition of valvular interstitial cells(VICs)in aortic valve.Moreover,diet-induction accelerated interleukin 17 receptor A(IL17RA)activation in VICs.In an IL17A inhibition model,the treatment group was intra-peritoneally injected with anti-IL17A mAb while controls received irrelevant antibody.Functional blockade of IL17A markedly reduced cellular infiltration and transition in aortic valve.To investigate potential mechanisms,NF-kB was co-stained in IL17RA^+VICs and IL17RA macrophages,and further confirmed by Western blotting in VICs.High-fat diet could activate NF-kB nuclear translocation in IL17RA^+VICs and IL17RA^+macrophages and this process was depressed after IL17A mAb-treatment.In conclusion,high-fat diet can lead to IL17A upregulation,VICs myofibroblastic transition and inflammatory cells infiltration in the aortic value of ApoE^-/-mice.Blocking IL17A with IL17A mAb can alleviate aortic valve inflammatory states.展开更多
目的探索初治慢性乙型肝炎(CHB)患者血清中细胞因子表达水平及其与病毒载量和肝脏炎症程度的关系,以期为临床动态评估CHB的病情和预后提供新思路。方法选择2018年10月至2019年11月就诊于海军军医大学(第二军医大学)第一附属医院感染科...目的探索初治慢性乙型肝炎(CHB)患者血清中细胞因子表达水平及其与病毒载量和肝脏炎症程度的关系,以期为临床动态评估CHB的病情和预后提供新思路。方法选择2018年10月至2019年11月就诊于海军军医大学(第二军医大学)第一附属医院感染科的初治慢性乙型肝炎病毒(HBV)感染者68例,健康对照者12名,通过ELISA检测血清中细胞因子IL-17A、IL-2、IL-21和IL-4表达水平,化学发光法检测HBV血清学标志物,qPCR法检测血清HBV DNA定量,全自动生化分析仪检测肝功能指标。采用Spearman相关分析评估血清细胞因子与病毒载量及肝脏炎症程度的相关性,绘制ROC曲线评价血清细胞因子水平对肝脏炎症程度的判断效能。结果相较于健康对照者,初治CHB患者血清IL-17A[17.50(11.99,25.36)pg/mL vs 13.74(9.07,16.94)pg/mL,Z=-2.001,P=0.045]、IL-21[37.12(23.85,77.66)pg/mL vs 20.30(17.90,24.19)pg/mL,Z=-3.485,P<0.01]水平升高,IL-2[57.19(31.10,79.92)pg/mL vs 73.06(62.41,105.84)pg/mL,Z=-2.509,P=0.012]水平降低,IL-4[11.40(5.79,18.62)pg/mL vs 10.84(8.05,25.20)pg/mL,Z=-0.681,P=0.496]水平差异无统计学意义。不同病程CHB患者的IL-17A表达水平差异有统计意义(H=8.870,P=0.031)。与非活动状态患者相比,炎症活动状态CHB患者血清中IL-17A[17.71(12.25,27.92)pg/mL vs 16.51(6.29,20.22)pg/mL]和IL-21[39.29(24.71,83.19)pg/mL vs 25.06(19.37,49.43)pg/mL]水平升高、IL-2[57.19(31.10,77.68)pg/mL vs 71.24(48.07,117.39)pg/mL]水平下降(均P<0.05),IL-4[11.40(5.94,18.12)pg/mL vs 14.57(3.12,24.49)pg/mL]水平差异无统计学意义(P>0.05)。HBeAg阳性CHB患者、HBeAg阴性CHB患者血清IL-17A[15.34(10.65,25.04)、19.98(15.55,34.14)pg/mL vs 13.74(9.07,16.94)pg/mL,H=10.061,P=0.007]和IL-21[37.74(25.06,82.87)、51.74(23.32,83.82)pg/mL vs 20.30(17.90,24.19)pg/mL,H=12.444,P=0.002]水平高于健康对照者,IL-2[57.19(37.45,79.92)、37.45(18.32,73.06)pg/mL vs 73.06(62.41,105.84)pg/mL,H=6.576,P=0.037]水平低于健康对照者。初治CHB患者血清IL-17A、IL-21、IL-4水平与HBV DNA定量无相关性(r=0.02、0.23、0.07,均P>0.05),IL-2水平与HBV DNA定量存在弱相关性(r=0.32,P=0.01)。初治CHB患者血清IL-17A、IL-21水平与丙氨酸转氨酶(ALT)水平(r=0.59、0.49,均P<0.01)和天冬氨酸转氨酶(AST)水平(r=0.47、0.36,均P<0.01)均存在相关性,而IL-2、IL-4水平与ALT、AST水平均无相关性(均P>0.05)。ALT≥300 U/L初治CHB组、ALT<300 U/L初治CHB组及健康对照组间血清IL-17A、IL-2、IL-21水平差异有统计学意义(均P<0.05),其中ALT≥300 U/L初治CHB组IL-17A、IL-21水平均高于ALT<300 U/L初治CHB组及健康对照组(均P<0.01),ALT<300 U/L初治CHB组IL-2水平低于健康对照组、IL-21水平高于健康对照组(均P<0.01)。ROC曲线分析结果显示,IL-17A判断肝脏炎症程度的AUC值为0.8933(95%CI 0.7930~0.9936),IL-21判断肝脏炎症程度的AUC值为0.7600(95%CI 0.6227~0.8973)。结论IL-17A、IL-2和IL-21参与慢性HBV感染进程。初治CHB患者无论HBeAg阳性与否或炎症程度高低,血清IL-17A和IL-21水平均升高,IL-2水平均下降;IL-2与HBV DNA定量有一定相关性;IL-17A和IL-21与ALT及AST均存在正相关;检测IL-17A和IL-2有助于病情评估与预后判断。展开更多
基金supported by the Natural Science Foundation of Jiangsu Province of China, No.BK20180948(to ZL)Nantong Applied Research Program of China, No.MS12019011(to XXF)Science and Technology Project of Nantong University of China, No.TDYXY2019007(to XXF)
文摘Interleukin 17A(IL-17A)was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications.However,the role of IL-17A in diabetic encephalopathy remains poorly understood.In this study,we established a mouse model of diabetic encephalopathy that was deficient in IL-17A by crossing Il17a-/-mice with spontaneously diabetic Ins2^(Akita)(Akita)mice.Blood glucose levels and body weights were monitored from 2-32 weeks of age.When mice were 32 weeks of age,behavioral tests were performed,including a novel object recognition test for assessing short-term memory and learning and a Morris water maze test for evaluating hippocampus-dependent spatial learning and memory.IL-17A levels in the serum,cerebrospinal fluid,and hippocampus were detected with enzyme-linked immunosorbent assays and real-time quantitative polymerase chain reaction.Moreover,proteins related to cognitive dysfunction(amyloid precursor protein,β-amyloid cleavage enzyme 1,p-tau,and tau),apoptosis(caspase-3 and-9),inflammation(inducible nitric oxide synthase and cyclooxygenase 2),and occludin were detected by western blot assays.Pro-inflammatory cytokines including tumor necrosis factor-α,interleukin-1β,and interferon-γin serum and hippocampal tissues were measured by enzyme-linked immunosorbent assays.Microglial activation and hippocampal neuronal apoptosis were detected by immunofluorescent staining.Compared with that in wild-type mice,mice with diabetic encephalopathy had higher IL-17A levels in the serum,cerebrospinal fluid,and hippocampus;downregulation of occludin expression;lower cognitive ability;greater loss of hippocampal neurons;increased microglial activation;and higher expression of inflammatory factors in the serum and hippocampus.IL-17A knockout attenuated the abovementioned changes in mice with diabetic encephalopathy.These findings suggest that IL-17A participates in the pathological process of diabetic encephalopathy.Furthermore,IL-17A deficiency reduces diabetic encephalopathy-mediated neuroinflammation and cognitive defects.These results highlight a role for IL-17A as a mediator of diabetic encephalopathy and potential target for the treatment of cognitive impairment induced by diabetic encephalopathy.
基金This project was supported by grants from the National Key Research and Development Program of China(No.2016YFA0101100)National Natural Science Foundation of China(No.81700339 and No.31330029)Scientific Research Training Program for Young Talents sponsored by Union Hospital,Tongji Medical College,Huazhong University of Science and Technology。
文摘Summary:Interleukin 17A(IL 17A)is reported to be involved in many inflammatory processes,but its role in aortic valve diseases remains unknown.We examined the role of IL17A based on an ApoE^-/-mouse model with strategies as fed with high-fat diet or treated with ILI7A monoclonal antibody(mAb).12 weeks of high-fat diet feeding can elevate cytokines secretion,inflammatory cells infiltration and myofibroblastic transition of valvular interstitial cells(VICs)in aortic valve.Moreover,diet-induction accelerated interleukin 17 receptor A(IL17RA)activation in VICs.In an IL17A inhibition model,the treatment group was intra-peritoneally injected with anti-IL17A mAb while controls received irrelevant antibody.Functional blockade of IL17A markedly reduced cellular infiltration and transition in aortic valve.To investigate potential mechanisms,NF-kB was co-stained in IL17RA^+VICs and IL17RA macrophages,and further confirmed by Western blotting in VICs.High-fat diet could activate NF-kB nuclear translocation in IL17RA^+VICs and IL17RA^+macrophages and this process was depressed after IL17A mAb-treatment.In conclusion,high-fat diet can lead to IL17A upregulation,VICs myofibroblastic transition and inflammatory cells infiltration in the aortic value of ApoE^-/-mice.Blocking IL17A with IL17A mAb can alleviate aortic valve inflammatory states.
文摘目的探索初治慢性乙型肝炎(CHB)患者血清中细胞因子表达水平及其与病毒载量和肝脏炎症程度的关系,以期为临床动态评估CHB的病情和预后提供新思路。方法选择2018年10月至2019年11月就诊于海军军医大学(第二军医大学)第一附属医院感染科的初治慢性乙型肝炎病毒(HBV)感染者68例,健康对照者12名,通过ELISA检测血清中细胞因子IL-17A、IL-2、IL-21和IL-4表达水平,化学发光法检测HBV血清学标志物,qPCR法检测血清HBV DNA定量,全自动生化分析仪检测肝功能指标。采用Spearman相关分析评估血清细胞因子与病毒载量及肝脏炎症程度的相关性,绘制ROC曲线评价血清细胞因子水平对肝脏炎症程度的判断效能。结果相较于健康对照者,初治CHB患者血清IL-17A[17.50(11.99,25.36)pg/mL vs 13.74(9.07,16.94)pg/mL,Z=-2.001,P=0.045]、IL-21[37.12(23.85,77.66)pg/mL vs 20.30(17.90,24.19)pg/mL,Z=-3.485,P<0.01]水平升高,IL-2[57.19(31.10,79.92)pg/mL vs 73.06(62.41,105.84)pg/mL,Z=-2.509,P=0.012]水平降低,IL-4[11.40(5.79,18.62)pg/mL vs 10.84(8.05,25.20)pg/mL,Z=-0.681,P=0.496]水平差异无统计学意义。不同病程CHB患者的IL-17A表达水平差异有统计意义(H=8.870,P=0.031)。与非活动状态患者相比,炎症活动状态CHB患者血清中IL-17A[17.71(12.25,27.92)pg/mL vs 16.51(6.29,20.22)pg/mL]和IL-21[39.29(24.71,83.19)pg/mL vs 25.06(19.37,49.43)pg/mL]水平升高、IL-2[57.19(31.10,77.68)pg/mL vs 71.24(48.07,117.39)pg/mL]水平下降(均P<0.05),IL-4[11.40(5.94,18.12)pg/mL vs 14.57(3.12,24.49)pg/mL]水平差异无统计学意义(P>0.05)。HBeAg阳性CHB患者、HBeAg阴性CHB患者血清IL-17A[15.34(10.65,25.04)、19.98(15.55,34.14)pg/mL vs 13.74(9.07,16.94)pg/mL,H=10.061,P=0.007]和IL-21[37.74(25.06,82.87)、51.74(23.32,83.82)pg/mL vs 20.30(17.90,24.19)pg/mL,H=12.444,P=0.002]水平高于健康对照者,IL-2[57.19(37.45,79.92)、37.45(18.32,73.06)pg/mL vs 73.06(62.41,105.84)pg/mL,H=6.576,P=0.037]水平低于健康对照者。初治CHB患者血清IL-17A、IL-21、IL-4水平与HBV DNA定量无相关性(r=0.02、0.23、0.07,均P>0.05),IL-2水平与HBV DNA定量存在弱相关性(r=0.32,P=0.01)。初治CHB患者血清IL-17A、IL-21水平与丙氨酸转氨酶(ALT)水平(r=0.59、0.49,均P<0.01)和天冬氨酸转氨酶(AST)水平(r=0.47、0.36,均P<0.01)均存在相关性,而IL-2、IL-4水平与ALT、AST水平均无相关性(均P>0.05)。ALT≥300 U/L初治CHB组、ALT<300 U/L初治CHB组及健康对照组间血清IL-17A、IL-2、IL-21水平差异有统计学意义(均P<0.05),其中ALT≥300 U/L初治CHB组IL-17A、IL-21水平均高于ALT<300 U/L初治CHB组及健康对照组(均P<0.01),ALT<300 U/L初治CHB组IL-2水平低于健康对照组、IL-21水平高于健康对照组(均P<0.01)。ROC曲线分析结果显示,IL-17A判断肝脏炎症程度的AUC值为0.8933(95%CI 0.7930~0.9936),IL-21判断肝脏炎症程度的AUC值为0.7600(95%CI 0.6227~0.8973)。结论IL-17A、IL-2和IL-21参与慢性HBV感染进程。初治CHB患者无论HBeAg阳性与否或炎症程度高低,血清IL-17A和IL-21水平均升高,IL-2水平均下降;IL-2与HBV DNA定量有一定相关性;IL-17A和IL-21与ALT及AST均存在正相关;检测IL-17A和IL-2有助于病情评估与预后判断。
