PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■创伤后应激障碍（PTSD）是一种使人衰弱的心理障碍，也表现为神经免疫不规则。患者表现出升高的交感神经紧张，并且发生继发性自身免疫性疾病的风险增加。以前,使用创伤后应激障碍的临床前模型，我们证明,T淋巴细胞的交感神经信号的消除特别限制了它们产生促炎白细胞介素17A(IL-17A)的能力;IL-17A是一种参与许多自身免疫性疾病发展的细胞因子.然而,交感神经信号与T淋巴细胞IL-17A产生的相关机制尚不清楚.
■使用反复的社会失败压力（RSDS）的修改版本，允许男性和女性，我们评估了肾上腺素能受体阻断(遗传和药理学)和儿茶酚胺耗竭对T淋巴细胞IL-17A生成的影响.此外,我们研究了肾上腺素能信号和T淋巴细胞产生的儿茶酚胺对体外分化为产生IL-17A的表型的CD4+和CD8+T淋巴细胞的影响.
■只有对β1和2肾上腺素能受体（β1/2）的药物抑制才能显着降低RSDS后循环IL-17A的水平，但不影响其他促炎细胞因子(例如，IL-6,TNF-α,和IL-10）。使用RSDS与全球β1/2受体敲除小鼠一起证实了这一发现，以及通过过继转移β1/2敲除的T淋巴细胞进入免疫缺陷宿主。此外，离体极化T淋巴细胞产生显著较少的IL-17A与β1/2信号的阻断，即使在缺乏外源性交感神经递质补充的情况下，这表明T淋巴细胞产生的儿茶酚胺可能参与IL-17A的产生。的确,儿茶酚胺在体内和离体的药理学消耗均消除了T淋巴细胞IL-17A的产生，这表明免疫产生的神经传递在促炎细胞因子产生中的重要性。
■我们的数据描述了β1/2肾上腺素能受体和自体儿茶酚胺信号在T淋巴细胞IL-17A产生过程中的新作用。这些发现为与IL-17A相关病理相关的精神病和自身免疫性疾病的药物治疗提供了新的靶标。
■使用反复的社会失败压力（RSDS）的修改版本，允许男性和女性，我们评估了肾上腺素能受体阻断(遗传和药理学)和儿茶酚胺耗竭对T淋巴细胞IL-17A生成的影响.此外,我们研究了肾上腺素能信号和T淋巴细胞产生的儿茶酚胺对体外分化为产生IL-17A的表型的CD4+和CD8+T淋巴细胞的影响.
■只有对β1和2肾上腺素能受体（β1/2）的药物抑制才能显着降低RSDS后循环IL-17A的水平，但不影响其他促炎细胞因子(例如，IL-6,TNF-α,和IL-10）。使用RSDS与全球β1/2受体敲除小鼠一起证实了这一发现，以及通过过继转移β1/2敲除的T淋巴细胞进入免疫缺陷宿主。此外，离体极化T淋巴细胞产生显著较少的IL-17A与β1/2信号的阻断，即使在缺乏外源性交感神经递质补充的情况下，这表明T淋巴细胞产生的儿茶酚胺可能参与IL-17A的产生。的确,儿茶酚胺在体内和离体的药理学消耗均消除了T淋巴细胞IL-17A的产生，这表明免疫产生的神经传递在促炎细胞因子产生中的重要性。
■我们的数据描述了β1/2肾上腺素能受体和自体儿茶酚胺信号在T淋巴细胞IL-17A产生过程中的新作用。这些发现为与IL-17A相关病理相关的精神病和自身免疫性疾病的药物治疗提供了新的靶标。
