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<p>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 <i>via</i> 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.</p>

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ADAM17 Supports Disinhibition of Pre-sympathetic Glutamatergic Neurons Through Microglial Chemotaxis

  • 期刊论文

  • 发表日期：

    2025年8月4日

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  • Jiawei Wang,
  • Zihan Qiu,
  • Yue Han,
  • Hanxue Wu,
  • Miao Yuan,
  • Yan Liu,
  • Huichao Wang,
  • Shenglan Yuan,
  • Dengfeng Gao,
  • Lina Sun,
  • Xingjuan Chen,
  • Eric Lazartigues,
  • Fanni Li,
  • Rui Yang,
  • Jiaxi Xu

摘要

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.