ADAM17 in glutamatergic presympathetic neurons enhance angiotensin II-induced disinhibition and sympatho-excitation through microglia and chemotactic pathway

Background: Neuron-expressing ADAM17 (a disintegrin and metalloprotease 17) has been shown to support sympatho-excitation and salt-sensitive hypertension. The aim of current work was to identify by what mechanism ADAM17 in glutamatergic neurons support activation of presympathetic neurons (PSN). Methods: Both acute Ang-II stimulation in the PVN (paraventricular nucleus) and DOCA (deoxycorticosterone acetate)-salt model were utilized for electrophysiological recording and blood pressure (BP) recording, in mice with ADAM17 selective knockout in glutamatergic neurons (A17G), and ADAM17 targeted knockout in certain glutamatergic PVN-RVLM (rostral ventrolateral medulla) projecting neurons (PSN-A17G). Results: Both Ang-II and DOCA-salt treatment markedly decreased GABAergic inhibitory tone in the PVN of WT (wild-type) mice. Post DOCA-salt treatment, microglia were activated in the PVN, with significantly more expression of CD68 and related cytokines. With 7-day of DOCA-salt treatment, before BP arrived its plateau, PVN microglia had already been activated, and they were spotted more closely to virus-labeled glutamatergic PSN. Moreover, the number of GABAergic presynaptic terminals, locating on the soma area of PSN, was markedly reduced. In both A17G and PSN-A17G, these DOCA-salt-associated changes were blunted. Further experiments revealed that Ang-II promotes neuron-mediated chemotaxis for microglia, and this effect in neurons involved ADAM17 and its downstream – CX3CL1/CX3CR1 chemotactic pathway. Pharmacologically blocking CX3CR, or inhibiting migration of microglia, confirmed the contribution of CX3CL1/CX3CR1 signaling pathway and microglial displacement to Ang-II-induced disinhibition and activation of PSN.