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.

创伤后应激障碍（PTSD）是一种使人衰弱的精神疾病，会导致心理和身体健康发生有害变化。PTSD 患者特别容易受到危及生命的并发炎症驱动的病理（例如自身免疫）的影响，同时也表现出辅助性 T 17 (TH 17 ₎淋巴细胞驱动的炎症增加。虽然这种炎症增加的确切机制尚不清楚，但交感神经系统过度活跃是创伤后应激障碍的一个标志。交感神经系统的神经递质（即儿茶酚胺）可以改变 T 淋巴细胞功能，我们之前已证明其部分是由线粒体氧化还原介导的。此外，我们之前已经阐明，T 淋巴细胞产生自己的儿茶酚胺，并且纯化的 T 淋巴细胞中酪氨酸羟化酶（TH；儿茶酚胺合成的限速酶）和促炎白细胞介素 17A (IL-17A) 表达之间存在密切关联。心理创伤啮齿动物模型中的 T 淋巴细胞。因此，我们假设心理创伤期间 T 淋巴细胞产生的儿茶酚胺通过线粒体超氧化物依赖性机制驱动 T _H 17 T 淋巴细胞极化。为了测试这一点，T淋巴细胞特异性TH敲除小鼠（TH ^T-KO）利用重复的社交失败压力（RSDS）遭受心理创伤。RSDS 特征性地增加肿瘤坏死因子-α (TNFα)、IL-6、IL-17A 和 IL-22，然而，IL-17A 和 IL-22（T H 17 产生的细胞因子）在循环和 T-中选择性_减弱。 TH ^T-KO动物的淋巴细胞。当离体激活时，TH ^T-KO T淋巴细胞分泌的IL-17A和IL-22也被发现减少，但可以通过专门补充去甲肾上腺素来部分挽救。有趣的是，TH ^T-KO T淋巴细胞在外源极化条件下仍然能够极化至TH _{17 。}最后，与我们的假设相反，我们发现暴露于 RSDS 的 TH ^T-KO T 淋巴细胞仍然表现出升高的线粒体超氧化物，表明线粒体超氧化物升高是 T 淋巴细胞 TH 诱导、活性和 T _H 17 调节的上游。总体而言，这些数据表明 T 淋巴细胞中的 TH 在 RSDS 诱导的 T _H 17 T 淋巴细胞中发挥着关键作用，并为 RSDS 中的炎症提供了先前未描述的调节剂。