Biology subjects

Moshfegh, C. M.

Publications and source records attributed to Moshfegh, C. M..

3 recordsLinked to original sources

bioRxiv2022

T-lymphocyte Tyrosine Hydroxylase Regulates TH 17 T-lymphocytes during Repeated Social Defeat Stress

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which results in deleterious changes to psychological and physical health. Patients with PTSD are especially susceptible to co-morbid inflammation-driven pathologies, such as autoimmunity, while also demonstrating increased T-helper 17 (TH17) lymphocyte-driven inflammation. While the exact mechanism of this increased inflammation is unknown, overactivity of the sympathetic nervous system is a hallmark of PTSD. Neurotransmitters of the sympathetic nervous system (i.e., catecholamines) can alter T-lymphocyte function, which we have previously demonstrated to be partially mitochondrial redox-mediated. Furthermore, we have previously elucidated that T-lymphocytes generate their own catecholamines, and strong associations exist between tyrosine hydroxylase (TH; the rate-limiting enzyme in the synthesis of catecholamines) and pro-inflammatory interleukin 17A (IL-17A) expression within purified T-lymphocytes in a preclinical rodent model of PTSD. Therefore, we hypothesized that T-lymphocyte-generated catecholamines drive TH17 T-lymphocyte polarization through a mitochondrial superoxide-dependent mechanism during psychological trauma. To test this, T-lymphocyte-specific TH knockout mice (THT-KO) were subjected to repeated social defeat stress (RSDS). RSDS characteristically increased tumor necrosis factor- (TNF), IL-6, IL-17A, and IL-22, however, IL-17A and IL-22 (TH17 produced cytokines) were selectively attenuated in circulation and in T-lymphocytes of THT-KO animals. When activated ex vivo, secretion of IL-17A and IL-22 by THT-KO T-lymphocytes was also found to be reduced, but could be partially rescued with supplementation of norepinephrine specifically. Interestingly, THT-KO T-lymphocytes were still able to polarize to TH17 under exogenous polarizing conditions. Last, contrary to our hypothesis, we found RSDS-exposed THT-KO T-lymphocytes still displayed elevated mitochondrial superoxide, suggesting increased mitochondrial superoxide is upstream of T-lymphocyte TH induction, activity, and TH17 regulation. Overall, these data demonstrate TH in T-lymphocytes plays a critical role in RSDS-induced TH17 T-lymphocytes and offer a previously undescribed regulator of inflammation in RSDS.

immunology↗

bioRxiv2021

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

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.

animal behavior and cognition↗

bioRxiv2020

Inflammation is a stronger predictor of psychological trauma exposure than behavior in repeated social defeat

Post-traumatic stress disorder (PTSD) is a psychiatric illness that results in an increased risk for a variety of inflammatory diseases. The exact etiology of this increased risk in unknown, and thus, several animal models have been developed to investigate the neuroimmune interactions of PTSD. Repeated social defeat stress (RSDS) is an established preclinical model of psychological trauma that recapitulates certain behavioral and inflammatory aspects of human PTSD. Furthermore, RSDS has been utilized to subgroup animals into susceptible and resilient populations based on one specific behavioral phenotype (i.e., social interaction). Herein, we conducted an extensive investigation of circulating inflammatory proteins after RSDS, and found significant elevations in various cytokines and chemokines after exposure to psychological trauma. When categorizing animals into either susceptible or resilient populations based on social interaction, we found no inflammatory or other behavioral differences between these subgroups. Furthermore, assessment of associations between all detectable inflammatory proteins and behavioral outputs found no significant correlation between social interaction parameters and inflammation. In contrast, we identified a panel of 5 circulating inflammatory proteins that showed significant associations with elevated zero maze parameters. Strikingly, these 5 circulating inflammatory proteins displayed a stronger predictive ability of psychological trauma exposure compared to any behavioral outcome. These findings provide new insights into inflammatory markers associated with RSDS, and their ability to predict psychological trauma exposure more robustly than commonly utilized behavioral paradigms. HighlightsO_LIRepeated social defeat stress (RSDS) reproducibly produces peripheral inflammation C_LIO_LIPeripheral inflammation is not coupled to social interaction testing parameters C_LIO_LISusceptible and resilient categorization does not reflect peripheral inflammation C_LIO_LIAnxiety-like behavioral parameters are linked to peripheral inflammation in RSDS C_LIO_LIPeripheral inflammation is more predictive of trauma than behavior in RSDS C_LI

animal behavior and cognition↗