Autonomic Regulation of T-Lymphocyte Inflammation after Psychological Trauma

Abstract

Post-traumatic stress disorder (PTSD) is a complex psychiatric condition that is accompanied by systemic inflammation, increased sympathetic activity, and an elevated risk of cardiovascular disease development. These physiological alterations hint at disturbances in the immune system, yet the precise signaling mechanisms linking psychological trauma to immune responses remain poorly understood. In a preclinical murine model of PTSD, termed repeated social defeat stress (RSDS), we previously demonstrated that psychological trauma induces systemic inflammation, notably the production of interleukin 17A (IL-17A) and 22 (IL-22) from T-lymphocytes. Targeted denervation of the spleen successfully abolished the T-lymphocyte inflammatory response following psychological trauma, suggesting a neural origin for the signal. Furthermore, we showed that T-lymphocytes lacking tyrosine hydroxylase (i.e., devoid of the ability to produce catecholamines) were unable to produce IL-17A and IL-22 after RSDS, further suggesting an autonomic role in the expression of these proinflammatory cytokines. Therefore, we postulated that psychological trauma elicits T-lymphocyte inflammation via sympathetic modulation. To investigate this hypothesis, we employed chemogenetic technology known as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to inhibit sympathetic signaling from the rostral ventrolateral medulla (RVLM), a central region of sympathetic signaling, during RSDS. RVLM DREADD-injected RSDS mice showed blunted blood pressure (-1.17 fold, p<0.0001) and heart rate (-1.07 fold, p=0.0026) compared to wild-type RSDS mice, confirming the effcacy of the sympathetic blockade. Moreover, after RSDS with sympathetic blockade, mice possessed completely ablated systemic circulating protein levels of IL-17A and IL-22 (-5.8 fold and -4.7 fold, respectively) compared to control GFP injected RSDS mice. To investigate the role of sympathetic regulation further, we next examined mice lacking beta 1 and 2-adrenergic receptors, given the previously described abundance of these receptors on T-lymphocytes. Confirming the results of the sympathetic blockade, mice lacking beta 1 and 2 adrenergic receptors had significantly diminished systemic circulating protein levels of IL-17A and IL-22 (-7.5 fold, p=0.0011; -31.5 fold, respectively) compared to wild-type mice after RSDS. Moreover, systemic infusion of the beta 1 and 2-adrenergic receptor antagonist propranolol also showed attenuated circulating levels of IL-17A and IL-22 (-2.57 fold and -14.59 fold, respectively) in wild-type mice after RSDS. Taken together, these data support a role for sympathetic modulation of T-lymphocyte inflammation after psychological trauma, which provides new insights into how mental health leads to somatic pathophysiology. R01HL158521. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.