Abstract 003: Selective Splenic Denervation Inhibits the Egression of T Cell From Spleen, Induced by Angiotensinii, and Protects From Hypertension

Abstract

It has been elucidated that immunity plays a role in both etiology and target organ damage of hypertension (HTN) induced by different stimuli (AngII, salt, etc.). In the very last year, we found that AngII activates a neuroimmune pathway, passing through the celiac ganglion (CG). Here, we aimed at dissecting this neuroimmune drive, in order to examine the specific role of splenic sympathetic nerve activity (SSNA) in the onset of HTN. We tested the hypothesis that chronic AngII infusion activates SSNA, in order to recruit T cells. In splenic nerve bundles, we recorded SSNA with a bipolar electrode in mice infused with AngII for 3 days (before BP increase) or with vehicle. SSNA was higher in AngII mice, as compared to vehicle (355±18 vs 141±24 spikes/10min) (p<0.001). We next selectively denervated splenic nerve (SDN) by thermoablation, in order to evaluate whether the AngII-induced increase in SSNA could be detrimental for activation of immunity and onset of HTN. We confirmed the efficacy of SDN by injecting a retrograde neurotracer in the spleen, which was effective in labeling the CG neurons only in sham mice and not in SDN. Furthermore, the tyrosine hydroxylase innervation in the splenic artery of SDN mice was reduced as compared to sham, as well as noradrenaline content in the spleen (sham: 1000±274 vs SDN: 172±44 pg/mg tissue, p<0.01). After 28 days from AngII infusion, SDN mice were protected from HTN as compared to sham (SBP: 107±2 vs 129±3 mmHg) and vehicle treated mice (veh-sham 110±1 vs veh-SDN 106±1 mmHg) (p<0.001). Moreover, SDN hampered the T cell egression from splenic reservoir, evaluated as CD3+ cell content, induced by AngII. In the end, we assessed the amount of T cells infiltration, finding that AngII-SDN mice were significantly protected in aorta (CD8+/mm2: veh-sham 197±17; veh-SDN 143±14; AngII-sham 293±36*; AngII-SDN 156±8) and kidney (CD8+/mm2: veh-sham 40±4; veh-SDN 34±4; AngII-sham 231±27*; AngII-SDN 29±5), *p<0.01 vs all other groups. Similar results were found for CD4+ infiltrates. Our results demonstrate that the neuroimmune drive activated by chronic AngII infusion is mediated by the activation of the SSNA, converging into T cells activation in the spleen and their egression toward target organs, where they contribute to the onset of HTN.