The role of circulating small extracellular vesicles in chronic psychosocial stress/ PTSD-related inflammation

• Applicants: Dr. Tim Eiseler; Dr. Dominik Langgartner
• Subject Area: Biological Psychiatry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560811947

Chronic psychosocial stress/ trauma is a major burden of modern life and poses a significant risk factor for the development of posttraumatic stress disorder (PTSD). Although the pathophysiological mechanisms behind the development of PTSD are not fully understood so far, an increasing number of preclinical and clinical studies indicates that stress-induced inflammation is involved in disease development. Therefore, all factors facilitating an individual’s immune activity are likely to increase their stress/ trauma vulnerability. A rather novel factor implicated in inflammatory modulation are small extracellular vesicles (sEVs, exosomes), which have recently been identified to have a vital function in propagating inflammation after severe physical trauma. Specifically, the latter is associated with the release of an increased amount of sEVs with altered cargo profile from endothelial cells, which locally and systemically propagate inflammation by transferring pro-inflammatory mRNAs and barrier-destabilizing miRNAs to other endothelial cells. In contrast to the role of sEVs in physical trauma, sEV functions in the pathogenesis of psychosocial stress-related disorders, like PTSD are still elusive. Interestingly, our preliminary data indicate that psychosocial trauma induced by the chronic subordinate colony housing (CSC) paradigm, a model for PTSD in mice, significantly increases circulating sEVs from endothelial cells, neutrophils, and T-cells. Moreover, a PTSD cytokine cocktail induced an enhanced sEV secretion from endothelial cells in vitro, which in turn mediated the expression of pro-inflammatory markers, like CxCl2 or ICAM-1 from other endothelial cells. Finally, injection of CSC-derived sEVs into naïve recipient mice was able to facilitate general anxiety-related behavior. We therefore aim to explore the hypothesis that sEVs are implicated in mediating psychosocial stress/ PTSD-related inflammation. To achieve this aim, we will i) investigate if psychosocial stress/PTSD-related systemic inflammation is propagated by quantitative and qualitative changes in sEV release, ii) determine sEV-mediated immunological, physiological and behavioral effects in mice injected with psychosocial trauma-derived sEVs as well as mice with inhibited sEV biogenesis and iii) examine if psychosocial trauma-derived sEVs are required for the development of stress-related immunological, physiological and behavioral effects.

• DFG Programme: Research Grants