ADAM17 Supports Disinhibition of Pre-sympathetic Glutamatergic Neurons Through Microglial Chemotaxis
Jiawei Wang1 · Zihan Qiu1 · Yue Han1 · Hanxue Wu1 · Miao Yuan2 · Yan Liu1 · Huichao Wang1 · Shenglan Yuan1 · Dengfeng Gao2 · Lina Sun3 · Xingjuan Chen4 · Eric Lazartigues5,6 · Fanni Li7 · Rui Yang1 · Jiaxi Xu1,2,8
1 Department of Physiology and Pathophysiology, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China
2 Department of Cardiology, Xi’an Jiaotong University Second Afliated Hospital, Xi’an 710004, China
3 Department of Pathogenic Microbiology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China
4 Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, China
5 Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
6 SouthEast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA
7 Department of Talent Highland, The First Afliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
8 Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
Abstract
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.
Keywords
ADAM17; Central nervous system; Angiotensin II; Chemotaxis; Salt-sensitive hypertension
