Department of Neuroscience, University of Florida College of Medicine, Gainesville, Florida, USA.
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
JCI Insight. 2022 Feb 22;7(4):e151892. doi: 10.1172/jci.insight.151892.
Monocyte-derived macrophages (MDMs) are key players in tissue homeostasis and diseases regulated by a variety of signaling molecules. Recent literature has highlighted the ability for biogenic amines to regulate macrophage functions, but the mechanisms governing biogenic amine signaling in and around immune cells remain nebulous. In the CNS, biogenic amine transporters are regarded as the master regulators of neurotransmitter signaling. While we and others have shown that macrophages express these transporters, relatively little is known of their function in these cells. To address these knowledge gaps, we investigated the function of norepinephrine transporter (NET) and dopamine transporter (DAT) on human MDMs. We found that both NET and DAT are present and can uptake substrate from the extracellular space at baseline. Not only was DAT expressed in cultured MDMs, but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immunomodulatory mechanism in response to LPS. LPS induced reverse transport of dopamine through DAT, engaging an autocrine/paracrine signaling loop that regulated the macrophage response. Removing this signaling loop enhanced the proinflammatory response to LPS. Our data introduce a potential role for DAT in the regulation of innate immunity.
单核细胞衍生的巨噬细胞（MDMs）是受多种信号分子调节的组织内稳态和疾病的关键参与者。最近的文献强调了生物胺调节巨噬细胞功能的能力，但生物胺信号在免疫细胞内外的调控机制仍不清楚。在中枢神经系统中，生物胺转运体被认为是神经递质信号的主要调节因子。虽然我们和其他人已经表明巨噬细胞表达这些转运体，但它们在这些细胞中的功能相对知之甚少。为了解决这些知识空白，我们研究了去甲肾上腺素转运体（NET）和多巴胺转运体（DAT）在人 MDMs 中的功能。我们发现 NET 和 DAT 均存在，并能在基线时从细胞外空间摄取底物。DAT 不仅在培养的 MDMs 中表达，而且在原位的一部分肠道巨噬细胞中也有检测到。令人惊讶的是，我们发现了一种 NET 独立、DAT 介导的免疫调节机制，对 LPS 有反应。LPS 通过 DAT 诱导多巴胺的反向转运，参与调节巨噬细胞反应的自分泌/旁分泌信号环。去除这个信号环增强了对 LPS 的促炎反应。我们的数据为 DAT 在先天免疫调节中的作用提供了一个新的视角。
