T-lymphocyte Tyrosine Hydroxylase Regulates T H 17 T-lymphocytes During Repeated Social Defeat Stress

Authors

Safwan K. Elkhatib, University of Nebraska Medical Center
Cassandra M. Moshfegh, University of Nebraska Medical CenterFollow
Gabrielle F. Watson, University of Nebraska Medical CenterFollow
Adam J. Case, Texas A&M Health Science Center

Document Type

Article

Journal Title

Brain, Behavior, and Immunity

Publication Date

2022

Volume

104

Abstract

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 life-threatening co-morbid inflammation-driven pathologies, such as autoimmunity, while also demonstrating increased T-helper 17 (T_H17) 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 rodent model of psychological trauma. Therefore, we hypothesized that T-lymphocyte-generated catecholamines drive T_H17 T-lymphocyte polarization through a mitochondrial superoxide-dependent mechanism during psychological trauma. To test this, T-lymphocyte-specific TH knockout mice (TH^T-KO) were subjected to psychological trauma utilizing repeated social defeat stress (RSDS). RSDS characteristically increased tumor necrosis factor-α (TNFα), IL-6, IL-17A, and IL-22, however, IL-17A and IL-22 (T_H17 produced cytokines) were selectively attenuated in circulation and in T-lymphocytes of TH^T-KO animals. When activated ex vivo, secretion of IL-17A and IL-22 by TH^T-KO T-lymphocytes was also found to be reduced, but could be partially rescued with supplementation of norepinephrine specifically. Interestingly, TH^T-KO T-lymphocytes were still able to polarize to T_H17 under exogenous polarizing conditions. Last, contrary to our hypothesis, we found RSDS-exposed TH^T-KO T-lymphocytes still displayed elevated mitochondrial superoxide, suggesting increased mitochondrial superoxide is upstream of T-lymphocyte TH induction, activity, and T_H17 regulation. Overall, these data demonstrate TH in T-lymphocytes plays a critical role in RSDS-induced T_H17 T-lymphocytes and offer a previously undescribed regulator of inflammation in RSDS.

DOI Link

10.1016/j.bbi.2022.05.007

ISSN

1090-2139

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Recommended Citation

Elkhatib, Safwan K.; Moshfegh, Cassandra M.; Watson, Gabrielle F.; and Case, Adam J., "T-lymphocyte Tyrosine Hydroxylase Regulates T H 17 T-lymphocytes During Repeated Social Defeat Stress" (2022). Journal Articles: Cellular & Integrative Physiology. 42.
https://digitalcommons.unmc.edu/com_cell_articles/42