Redox‐Driven Lymphocyte Inflammation Sensitizes Mice to Psychological Stress‐Mediated Hypertension

Abstract

Post‐traumatic stress disorder (PTSD) is a debilitating psychological disease associated with increased activation of the sympathetic nervous system and norepinephrine (NE) outflow. PTSD increases the risk of cardiovascular diseases like hypertension by over 50%, but the mechanisms controlling this predisposition remain unclear. It is now well‐accepted that hypertension is regulated in part due to immune system‐driven inflammation, and our laboratory has previously reported that exposure to exogenous NE can modulate levels of T‐lymphocyte pro‐inflammatory cytokines (i.e. IL‐17A and IL‐6). Due to this, we hypothesized that the increased sympathoexcitation observed in PTSD drives pro‐inflammatory cytokine production from lymphocytes, and this inflammation leads to a susceptibility to hypertension. Using a mouse model of PTSD‐like psychological stress, we have demonstrated a two‐stage hypertensive phenotype. First, a modest but sustained increase in mean arterial pressure immediately following the stress induction (+9.8 mmHg, p=0.029 vs. controls). Second, a sensitization to low‐dose angiotensin II (AngII) after termination of the stress induction, which resulted in a more pronounced increase in blood pressure (+17.9 mmHg, p=0.002 vs. controls). To assess the physiological changes after psychological stress that may contribute to this increased blood pressure, we first assessed the activation status of the sympathetic nervous system. Interestingly, stressed mice demonstrated no appreciable change in circulating NE content, but splenic NE content was increased 2.5 fold vs. controls (p=0.019). Moreover, splenic tyrosine hydroxylase was increased 4.1 fold over control spleens (p=0.0009), inferring sustained sympathetic activation to this secondary lymphoid organ. Due to this, we next measured an array of circulating pro‐inflammatory cytokines, and observed increases in IL‐17A (+3.1 fold, p=0.011), IL‐22 (+1.9 fold, p=0.034), IL‐6 (+4.8 fold, p=0.063), and TNFα (+1.8 fold, p=0.021) following stress induction, which suggests a lymphocyte‐driven pro‐inflammatory cascade occurring in psychologically stressed animals. We have previously demonstrated that exogenous NE may modulate pro‐inflammatory cytokine production in T‐lymphocytes via alterations in redox signaling, thus, we assessed the redox status of splenocytes in stressed and control animals. Splenic lymphocytes from stressed mice demonstrated increases in both dihydroethidium (+2.1 fold, p=0.012) and MitoSOX Red (+2.2 fold, p=0.004) fluorescence, signifying a potentially novel role for immune activation via reactive oxygen species in vivo. Last, to assess the causal role of lymphocytes in driving the predisposition to hypertension during psychological stress, we utilized recombination activating gene 2 (Rag2) knock‐out animals, which are devoid of mature lymphocytes. Preliminary studies exposing these animals to psychological stress demonstrated attenuated cardiovascular and inflammatory alterations compared to wild‐type controls, which suggests lymphocytes play a direct role in regulating the stress‐induced pro‐inflammatory environment leading to increased blood pressure. Overall, our data suggest the potential for a new paradigm involving redox control of lymphocytes in the regulation of psychological stress‐driven hypertension.Support or Funding InformationThis work supported by NIH R00HL123471 and the Mary G. and George W. White Fund for Medical ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.