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bioRxiv · 10.1101/2021.01.16.426952

Splenic denervation attenuates repeated social defeat stress-induced T-lymphocyte inflammation

Elkhatib, S. K.·Moshfegh, C. M.·Watson, G. F.·Schwab, A. D.·Katsurada, K.·Patel, K. P.·Case, A. J.
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Abstract

BackgroundPost-traumatic stress disorder (PTSD) is a devastating psychological disorder that significantly increases the risk for inflammatory diseases. While the exact etiology of this predisposition remains unclear, PTSD canonically increases overall sympathetic tone resulting in increased norepinephrine (NE) outflow. Previously, we demonstrated that exogenous NE alters mitochondrial superoxide in T-lymphocytes to produce a pro-inflammatory T-helper 17 (TH17) phenotype. Therefore, we hypothesized sympathetic-driven neuroimmune interactions could mediate psychological trauma-induced T-lymphocyte inflammation. MethodsRepeated social defeat stress (RSDS) is a preclinical murine model that recapitulates the behavioral, autonomic, and inflammatory aspects of PTSD. Targeted splenic denervation (Dnx) was performed to deduce the contribution of splenic sympathetic nerves to RSDS-induced inflammation. Eighty-five C57BL/6J mice underwent Dnx or sham-operation, followed by RSDS or control paradigms. Animals were assessed for behavioral, autonomic, inflammatory, and redox profiles. ResultsDnx did not alter the antisocial or anxiety-like behavior induced by RSDS. In circulation, RSDS Dnx animals exhibited diminished levels of T-lymphocyte-specific cytokines (IL-2, IL-17A, and IL-22) compared to intact animals, whereas other non-specific inflammatory cytokines (e.g., IL-6, TNF-, and IL-10) were unaffected by Dnx. Importantly, Dnx specifically ameliorated the increases in RSDS-induced T-lymphocyte mitochondrial superoxide, TH17 polarization, and pro-inflammatory gene expression with minimal impact to non-T-lymphocyte immune populations. ConclusionsOverall, our data suggest that sympathetic nerves regulate RSDS-induced splenic T-lymphocyte inflammation, but play a minimal role in the behavioral and non-T-lymphocyte inflammatory phenotypes induced by this psychological trauma paradigm.

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Elkhatib, S. K., Moshfegh, C. M., Watson, G. F., Schwab, A. D., Katsurada, K., Patel, K. P., Case, A. J.. 2021-01-19. Splenic denervation attenuates repeated social defeat stress-induced T-lymphocyte inflammation. https://doi.org/10.1101/2021.01.16.426952

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