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.
Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Brain Behav Immun. 2025 Jan;123:1061-1070. doi: 10.1016/j.bbi.2024.11.013. Epub 2024 Nov 13.
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 mouse model of repeated social defeat stress (RSDS) that recapitulates certain features 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 RSDS that allows for both males and females, as well as ex vivo models of T-lymphocyte polarization, we assessed the impact and mechanism of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte differentiation to IL-17A-producing subtypes (i.e., T17).
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. 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. Furthermore, cyclic AMP (cAMP) was demonstrated to be mechanistically involved in driving IL-17A production in T-lymphocytes, and amplifying cAMP signaling could restore IL-17A deficits caused by the absence of β1/2 signaling. Last, removal of β1/2 and cAMP signaling, even in IL-17A polarizing conditions, promoted regulatory T-lymphocyte (Treg) polarization, suggesting adrenergic signaling plays a role in the switching between pro- and anti-inflammatory T-lymphocyte subtypes.
Our data depict a novel role for β1/2 adrenergic and cAMP signaling in the balance of T17/Treg lymphocytes. 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，还伴有神经免疫异常。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，我们利用一种重复社会挫败应激（RSDS）的小鼠模型，该模型概括了PTSD的某些特征，证明消除向T淋巴细胞的交感神经信号传导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产生之间的机制仍不清楚。
使用一种改良的RSDS模型，该模型适用于雄性和雌性小鼠，以及T淋巴细胞极化的体外模型，我们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淋巴细胞分化为产生IL-17A的亚型（即T17）的影响和机制。
只有对β1和β2肾上腺素能受体（β1/2）的药理学抑制在RSDS后显著降低了循环IL-17A水平，但不影响其他促炎细胞因子（如IL-6、TNF-α和IL-10）。使用全局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。体外极化的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。此外，环磷酸腺苷（cAMP）被证明在机制上参与驱动T淋巴细胞中IL-17A的产生，增强cAMP信号传导可以恢复由β1/2信号缺失引起的IL-17A缺陷。最后，即使在IL-17A极化条件下，去除β1/2和cAMP信号传导也会促进调节性T淋巴细胞（Treg）极化，表明肾上腺素能信号传导在促炎和抗炎T淋巴细胞亚型之间的转换中起作用。
我们的数据描绘了β1/2肾上腺素能和cAMP信号传导在T17/Treg淋巴细胞平衡中的新作用。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。
