A disintegrin and metalloprotease 17(ADAM17)is a membrane-bound enzyme that cleaves cell-surface proteins.Here,we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inp...A disintegrin and metalloprotease 17(ADAM17)is a membrane-bound enzyme that cleaves cell-surface proteins.Here,we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub,located in the paraventricular nucleus of the hypothalamus(PVN),upon stimulation by angiotensin II(Ang-II).For Ang-II-induced disinhibition,targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons.Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17.Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II’s pressor response.Using conditional and targeted knockout models of ADAM17,an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension.Collectively,this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation.展开更多
去整合素-金属蛋白酶17(adisintegrin and metalloproteinase17,ADAM17)是近年来发现的金属蛋白酶解聚素(adisintegrinand metalloproteinase,ADAMs)家族成员之一,参与肿瘤发生发展的重要过程。去整合素-金属蛋白酶17(ADAM17)又称为肿...去整合素-金属蛋白酶17(adisintegrin and metalloproteinase17,ADAM17)是近年来发现的金属蛋白酶解聚素(adisintegrinand metalloproteinase,ADAMs)家族成员之一,参与肿瘤发生发展的重要过程。去整合素-金属蛋白酶17(ADAM17)又称为肿瘤坏死因子转换酶(TACE),因此除了具有解聚素和金属蛋白酶的活性,还可以将没有活性的肿瘤坏死因子(TNF-α)从细胞膜上切割下来,并与其受体相结合,从而激活TNF-α下游的EGFR信号传导,此外还可以激活多条信号传导途径如Notch传导通路等,进而影响肿瘤细胞的粘附、凋亡、转移、增殖等生物学行为。纵观ADAM17的研究,在多种恶性肿瘤中呈高表达状态,且这种高表达状态与肿瘤侵润程度及转移情况相关。随着人们对ADAM17基础科学的研究不断深入,ADAM17的临床应用前景也正被不断开发,鉴于其在多种恶性肿瘤组织中高表达的情况,可将其作为许多肿瘤的诊断标志物、及判断其转移和预后情况。靶向药物的研究给恶性肿瘤患者带来了新的福音,利用EGFR为研究扳机点成功研制出许多靶向药物,在EGFR的配体释放环节,ADAM17尤为重要。本文总结了ADAM17在恶性肿瘤发展中的作用及其机制,对其在癌症治疗的应用前景进行展望。展开更多
基金supported by the National Natural Science Foundation of China(82100454,32271016,82101586,and 81872563)the National Heart,Lung,Blood,and Sleep Institute(HL163588).
文摘A disintegrin and metalloprotease 17(ADAM17)is a membrane-bound enzyme that cleaves cell-surface proteins.Here,we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub,located in the paraventricular nucleus of the hypothalamus(PVN),upon stimulation by angiotensin II(Ang-II).For Ang-II-induced disinhibition,targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons.Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17.Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II’s pressor response.Using conditional and targeted knockout models of ADAM17,an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension.Collectively,this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation.
文摘去整合素-金属蛋白酶17(adisintegrin and metalloproteinase17,ADAM17)是近年来发现的金属蛋白酶解聚素(adisintegrinand metalloproteinase,ADAMs)家族成员之一,参与肿瘤发生发展的重要过程。去整合素-金属蛋白酶17(ADAM17)又称为肿瘤坏死因子转换酶(TACE),因此除了具有解聚素和金属蛋白酶的活性,还可以将没有活性的肿瘤坏死因子(TNF-α)从细胞膜上切割下来,并与其受体相结合,从而激活TNF-α下游的EGFR信号传导,此外还可以激活多条信号传导途径如Notch传导通路等,进而影响肿瘤细胞的粘附、凋亡、转移、增殖等生物学行为。纵观ADAM17的研究,在多种恶性肿瘤中呈高表达状态,且这种高表达状态与肿瘤侵润程度及转移情况相关。随着人们对ADAM17基础科学的研究不断深入,ADAM17的临床应用前景也正被不断开发,鉴于其在多种恶性肿瘤组织中高表达的情况,可将其作为许多肿瘤的诊断标志物、及判断其转移和预后情况。靶向药物的研究给恶性肿瘤患者带来了新的福音,利用EGFR为研究扳机点成功研制出许多靶向药物,在EGFR的配体释放环节,ADAM17尤为重要。本文总结了ADAM17在恶性肿瘤发展中的作用及其机制,对其在癌症治疗的应用前景进行展望。
