Abstract P304: A Sympathetic-cholinergic Pathway Performs a Connection Between Brain and Spleen, to Prime Immune System and Induce Arterial Hypertension

Abstract

It is now widely recognized that immune system has a crucial role in hypertension. Various studies have demonstrated that the activation of adaptive immunity, and in particular of T cells, is a crucial moment in the onset and maintaining of hypertension induced by various stimuli in mice. Our previous studies have shown that hypertensive stimuli couple the sympathetic nervous system to determine the activation of splenic immune system. However, how the brain-to-spleen connection is realized in hypertension remains unknown. In this study we demonstrate that mice subjected to various hypertensive stimuli (AngII, DOCA-salt) show an increase of sympathetic nervous activity recorded in vivo in the splenic nerve (Firing Frequency: AngII 131±17 vs Veh 30±10 spikes/10 min, p<0.001). We also show how the sympathetic pathway induced by pro-hypertensive stimuli has its origin in the brain, converging into the spleen through a cholinergic-sympathetic connection that is realized through the vagus-splenic nerve drive and mediated at the molecular level by cholinergic nicotinic receptors at the level of celiac ganglion. In fact, we show that in celiac vagotomized mice, i.e. mice subjected to a procedure inhibiting vagal efferents but not central afferents, the splenic nervous drive induced by AngII was absent (AngII+VagX 21±4 vs AngII+sham 148±29 spikes/10 min, p<0.001). The same result was shown in α7 cholinergic nicotinic receptor KO mice, a receptor typically expressed by neurons in the peripheral ganglia (α7nAChR KO AngII 43±8 vs WT AngII 141±27 spikes/10 min, p<0.01). Moreover, we found that this cholinergic-sympathetic pathway was necessary to allow the activation of T cell costimulation and egression upon hypertensive challenges. Our results highlight a cholinergic-sympathetic pathway played by vagus-splenic nerves and responsible for immune system activation in response to hypertensive stimuli. We believe our results are significant because they reveal a previously unknown sympathetic pathway in hypertension for the first time. The brain-to-spleen connection realized through a cholinergic-sympathetic nervous drive that resembles the cholinergic anti-inflammatory pathway identified by immunologists in endotoxemia.