ADAM17 on glutamatergic neurons contributes to peripheral immune activation through increasing sympathetic activity
Authors: Xu Jiaxi , Molinas Adrien , Zsombok Andrea , Lazartigues Eric 
Published: June 2021

The brain plays an important role in modulating sympathetic drive to individual organs, leading to changes to cardiac output and vascular resistance for blood pressure regulation. Moreover, the peripheral immune system is also regulated by the sympathetic nervous system, and it can be activated in case of sympathoexcitation. Within the central nervous system, A Disintegrin And Metalloprotease 17 (ADAM17) impairs the compensatory activity of angiotensin converting enzyme type 2 (ACE2) through ectodomain shedding during hypertension. Here, we hypothesize that neuronal ADAM17, especially in excitatory neurons, contributes to the activation of peripheral immune system through sympathoexcitation. Deoxycorticosterone (DOCA)‐salt treatment is known to produce hypertension through increased sympathetic activity. Using this model, we showed that sympathetic outflow was increased in C57Bl6/J male mice (14–16 week‐old, n=10) treated with DOCA‐salt (1mg/g body weight sc + 1% saline po for 3 weeks), producing pathological cardiac hypertrophy, vascular remodeling, and hypertension (+38 ±6 mmHg). In those mice, splenic sympathetic activity was found to be significantly elevated, as evidenced by the increase of tyrosine hydroxylase (TH) expression in spleen (DOCA:sham=3.3, P<0.01 vs. sham). Meanwhile, T lymphocytes, including CD3+/CD45+ and CD8+/CD3+ T cells, were increased, by ~3‐fold, in the circulation of those DOCA‐salt‐treated animals (n=10/group, P<0.05 vs. sham). To test our hypothesis, mice with ADAM17 selectively deleted on glutamatergic neurons, a major type of excitatory neurons, were generated (A17G, ADAM17fl/fl:vGluT2‐cre). In DOCA‐salt‐treated A17G mice, the expression of TH in spleen was significantly lower, compared to the controls (P<0.01 vs. control+DOCA). Due to the reduction of splenic sympathetic drive, no marked increase in either CD3+/CD45+ or CD8+/CD3+ was observed in the A17G mice after DOCA‐salt treatment (n=10/group). Urinary norepinephrine (NE) levels were measured in both A17G and controls, and the level of NE secretion in A17G mice was significantly lower (A17G+DOCA:control+DOCA=0.5, n=10/group, P<0.01 vs. control+DOCA), further confirming their blunted sympathetic activity during DOCA‐salt hypertension. Within the PVN of A17G mice, angiotensin II (1 μM)‐induced activation of pre‐sympathetic neurons was found to be blunted (whole‐cell patch‐clamp recording), implying the critical role of ADAM17‐mediated signaling in regulating neuronal excitability. In summary, our data provide evidence that ADAM17 activation on glutamatergic neurons contributes to the activation of the peripheral immune system through sympathoexcitation, thus promoting the deployment of inflammatory T‐cells to peripheral end organs during the development of hypertension.Support or Funding InformationThis study was supported in part by research grants from the National Institutes of Health (HL093178 to E.L. and COBRE P30GM106392), the department of Veterans Affairs (BX004294) and the Research Enhancement Program at LSUHSC‐NO.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.