Lauten Tatlock H, Elkhatib Safwan K, Natour Tamara, Reed Emily C, Jojo Caroline N, Case Adam J
Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States.
Department of Medical Physiology, Texas A&M University, Bryan, TX, United States.
bioRxiv. 2024 Jun 9:2024.06.05.597633. doi: 10.1101/2024.06.05.597633.
Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a preclinical model of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear.
Using a modified version of repeated social defeat stress (RSDS) that allows for both males and females, we assessed the impact of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte IL-17A generation. Additionally, we explored the impact of adrenergic signaling and T-lymphocyte-produced catecholamines on both CD4+ and CD8+ T-lymphocytes polarized to IL-17A-producing phenotypes ex vivo.
Only pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Furthermore, ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Indeed, pharmacological depletion of catecholamines both in vivo and ex vivo abrogated T-lymphocyte IL-17A production demonstrating the importance of immune-generated neurotransmission in pro-inflammatory cytokine generation.
Our data depict a novel role for β1/2 adrenergic receptors and autologous catecholamine signaling during T-lymphocyte IL-17A production. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.
创伤后应激障碍（PTSD）是一种使人衰弱的心理障碍，也存在神经免疫异常。患者表现出交感神经张力升高，患继发性自身免疫性疾病的风险增加。此前，我们利用PTSD的临床前模型证明，消除对T淋巴细胞的交感神经信号传导会特异性地限制其产生促炎白细胞介素17A（IL-17A）的能力；IL-17A是一种与许多自身免疫性疾病发展有关的细胞因子。然而，交感神经信号传导与T淋巴细胞IL-17A产生之间的联系机制仍不清楚。
我们使用了一种改良的重复社会挫败应激（RSDS）模型，该模型适用于雄性和雌性动物，评估了肾上腺素能受体阻断（基因和药理学方法）和儿茶酚胺耗竭对T淋巴细胞IL-17A生成的影响。此外，我们还探讨了肾上腺素能信号传导和T淋巴细胞产生的儿茶酚胺对离体极化到产生IL-17A表型的CD4+和CD8+ T淋巴细胞的影响。
只有对β1和β2肾上腺素能受体（β1/2）的药理学抑制能在RSDS后显著降低循环IL-17A水平，但不影响其他促炎细胞因子（如IL-6、TNF-α和IL-10）。使用全球β1/2受体敲除小鼠的RSDS以及将β1/2敲除的T淋巴细胞过继转移到免疫缺陷宿主中证实了这一发现。此外，离体极化的T淋巴细胞在阻断β1/2信号传导时产生的IL-17A显著减少，即使在没有外源性交感神经递质补充的情况下也是如此，这表明T淋巴细胞产生的儿茶酚胺可能参与IL-17A的产生。事实上，体内和体外儿茶酚胺的药理学耗竭消除了T淋巴细胞IL-17A的产生，证明了免疫产生的神经传递在促炎细胞因子产生中的重要性。
我们的数据揭示了β1/2肾上腺素能受体和自体儿茶酚胺信号传导在T淋巴细胞IL-17A产生过程中的新作用。这些发现为与IL-17A相关病理的精神疾病和自身免疫性疾病的药物治疗提供了新靶点。
