Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA.
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32611, USA.
Cells. 2023 Jan 10;12(2):269. doi: 10.3390/cells12020269.
The dopamine transporter (DAT) regulates the dimension and duration of dopamine transmission. DAT expression, its trafficking, protein-protein interactions, and its activity are conventionally studied in the CNS and within the context of neurological diseases such as Parkinson's Diseases and neuropsychiatric diseases such as drug addiction, attention deficit hyperactivity and autism. However, DAT is also expressed at the plasma membrane of peripheral immune cells such as monocytes, macrophages, T-cells, and B-cells. DAT activity via an autocrine/paracrine signaling loop regulates macrophage responses to immune stimulation. In a recent study, we identified an immunosuppressive function for DAT, where blockade of DAT activity enhanced LPS-mediated production of IL-6, TNF-α, and mitochondrial superoxide levels, demonstrating that DAT activity regulates macrophage immune responses. In the current study, we tested the hypothesis that in the DAT knockout mice, innate and adaptive immunity are perturbed. We found that genetic deletion of DAT (DAT) results in an exaggerated baseline inflammatory phenotype in peripheral circulating myeloid cells. In peritoneal macrophages obtained from DAT mice, we identified increased MHC-II expression and exaggerated phagocytic response to LPS-induced immune stimulation, suppressed T-cell populations at baseline and following systemic endotoxemia and exaggerated memory B cell expansion. In DAT mice, norepinephrine and dopamine levels are increased in spleen and thymus, but not in circulating serum. These findings in conjunction with spleen hypoplasia, increased splenic myeloid cells, and elevated MHC-II expression, in DAT mice further support a critical role for DAT activity in peripheral immunity. While the current study is only focused on identifying the role of DAT in peripheral immunity, our data point to a much broader implication of DAT activity than previously thought. This study is dedicated to the memory of Dr. Marc Caron who has left an indelible mark in the dopamine transporter field.
多巴胺转运体（DAT）调节多巴胺传递的幅度和持续时间。DAT 的表达、转运、蛋白-蛋白相互作用及其活性通常在中枢神经系统中以及帕金森病等神经退行性疾病和药物成瘾、注意力缺陷多动和自闭症等神经精神疾病的背景下进行研究。然而，DAT 也在外周免疫细胞的质膜上表达，如单核细胞、巨噬细胞、T 细胞和 B 细胞。通过自分泌/旁分泌信号转导环，DAT 活性调节巨噬细胞对免疫刺激的反应。在最近的一项研究中，我们确定了 DAT 的免疫抑制功能，阻断 DAT 活性增强了 LPS 介导的 IL-6、TNF-α 和线粒体超氧化物水平的产生，表明 DAT 活性调节巨噬细胞免疫反应。在本研究中，我们检验了 DAT 敲除小鼠的固有和适应性免疫受到干扰的假设。我们发现，DAT（DAT）的基因缺失导致外周循环髓样细胞中存在基线炎症表型过度放大。在从 DAT 小鼠获得的腹腔巨噬细胞中，我们发现 MHC-II 表达增加，对 LPS 诱导的免疫刺激的吞噬反应增强，基础和全身内毒素血症后 T 细胞群体受到抑制，记忆 B 细胞扩增增强。在 DAT 小鼠中，去甲肾上腺素和多巴胺水平在脾脏和胸腺中增加，但在循环血清中不增加。这些发现与脾脏发育不良、脾脏髓样细胞增加和 MHC-II 表达升高一起，进一步支持 DAT 活性在外周免疫中的关键作用。虽然本研究仅集中于确定 DAT 在周围免疫中的作用，但我们的数据表明 DAT 活性的作用范围比以前认为的要广泛得多。这项研究是为了纪念 Marc Caron 博士，他在多巴胺转运体领域留下了不可磨灭的印记。
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