Neuroimmune dynamics involved in the pathogenesis of hypertension after psychological trauma

PROJECT SUMMARY
Post-traumatic stress disorder (PTSD) is a debilitating psychological condition that increases the risk of
life-threatening comorbid inflammatory diseases such as hypertension by over 50%. The goal of this project is
to focus specifically on the neurological-T-lymphocyte mechanisms that regulate psychological trauma-induced
inflammation and the predisposition to hypertension. Previous results from our laboratory using a preclinical
model of PTSD known as repeated social defeat stress (RSDS) have demonstrated splenic T-lymphocytes as
a primary source of inflammation after psychological trauma. Furthermore, we identified that RSDS-mice
display a heightened blood pressure response to angiotensin II (AngII), which mimics the cardiovascular
disease sensitization observed in PTSD patients. Importantly, mice lacking T-lymphocytes were not sensitized
to AngII, which implies T-lymphocyte-driven inflammation as a mechanistic regulator of blood pressure after
RSDS. We have additionally elucidated tight links between pro-inflammatory cytokine production from T-
lymphocytes, sympathetic nervous system activation, the mitochondrial redox environment (primarily
superoxide) in T-lymphocytes, anxiety-like behavior, and the development of a blood pressure sensitization to
AngII, which suggests these physiological elements are mechanistically-intertwined. Given this information, we
will test the central hypothesis that increased sympathoexcitation after RSDS drives splenic T-
lymphocyte inflammation through increased mitochondrial superoxide to enhance sensitivity to
hypertension. Our Specific Aims will determine neuroimmune pathways and intracellular mechanisms that
control T-lymphocyte inflammation in the RSDS model of PTSD. The innovation in this proposal lies in the
concept of central and local autonomic control of T-lymphocytes regulating blood pressure sensitization, the
biological identification of mitochondrial superoxide regulating T-lymphocyte inflammation after psychological
trauma, and the technological advances of our new genetically-engineered animal models and
neuromodulation techniques. Overall, this project will reveal the impact of T-lymphocyte inflammation after
psychological trauma, and aims to utilize this evidence to inform clinical management of PTSD via earlier
cardiovascular screening or targeted therapeutic intervention.

Grant Number: 5R01HL158521-05
NIH Institute/Center: NIH
Principal Investigator: Adam Case