Elucidation of the Molecular Signal Linking Psychological Trauma to T-lymphocyte Inflammation

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that not only exhibits significant behavioral pathology, but also increases the likelihood of comorbid inflammatory conditions such as autoimmune and cardiovascular diseases. While PTSD patients experience heightened systemic inflammation, the exact link between psychological trauma and immune dysregulation remains to be elucidated. Our group has recapitulated the psychological trauma-induced inflammatory phenotype in a pre-clinical murine model of PTSD known as repeated social defeat stress (RSDS). Importantly, a key site of this inflammation appears to originate from T-lymphocytes in the spleen, and targeted splenic nerve denervation was able to completely prevent splenic T-lymphocyte inflammation after RSDS (p<0.0001). This critical observation suggests the T-lymphocyte response to psychological trauma is neural derived as opposed to circulating, therefore, we began systematic investigation into possible neural-derived signals that may lead to enhanced T-lymphocyte inflammation. To investigate whether the signal involves the T-cell receptor (TCR), we utilized OT-I and OT-II mice that possess non-mouse antigen-restricted TCRs. RSDS induced T-lymphocyte inflammation in these mice similar to wild-type, therefore, suggesting the signal is not antigenic in nature (p>0.05). Next, we examined the role of norepinephrine and adrenergic signaling using both pharmacological blockade and genetic knockouts of both alpha and beta adrenergic receptors, but this too was insuffcient to reverse the RSDS-induced T-lymphocyte inflammation (p>0.05). Following this, we examined the role of damage associated molecular patterns (DAMPs) by pharmacological blockade of the toll-like receptor 4 (TLR4), yet again, this intervention did not attenuate T-lymphocyte inflammation after RSDS (p>0.05). Last, our data suggests interleukin 6 (IL-6) is upregulated early after psychological trauma; therefore, we examined the role for cytokine-induced T-lymphocyte inflammation. Using anti-IL-6 antibodies during RSDS, T-lymphocyte inflammation appeared blunted compared to wild-type animals (p<0.05). Moreover, T-lymphocytes treated with only IL-6 expressed similar inflammation gene profiles as those from RSDS animals (p<0.05). Taken together, our data suggest IL-6 may be the T-lymphocyte inflammation-inducing signal, but additional studies are warranted to understand the exact source of IL-6 and mechanisms underlying IL-6’s ability to drive T-lymphocyte inflammation. 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.