Trace amine-associated receptor 1 (TAAR1) is an established neuroregulatory G protein-coupled receptor with recent studies suggesting additional functions related to immunomodulation. Our lab has previously investigated TAAR1 expression within cells of the innate immune system and herein we aim to further elucidate TAAR1 function in both peripherally-derived and CNS-resident macrophages. The selective TAAR1 agonist RO5256390 was used in combination with common damage associated molecular patterns (ATP and ADP) to observe the effect of TAAR1 agonism on modulating cytokine secretion and metabolic profiles. In mouse bone-marrow derived macrophages, TAAR1 agonism inhibited TNF secretion following ATP stimulation, which appeared to be downstream of an associated pro-inflammatory shift in metabolic profile and transcriptional regulation of TNF synthesis. In contrast, TAAR1 agonism had no effect on ADP-induced TNF and IL-6 secretion in mouse microglia in either the presence or absence of astrocytes. In summary, we report a novel interaction between TAAR1 and purinergic signaling in peripherally-derived, but not CNS-resident, macrophages. These findings provide the first evidence of trace aminergic and purinergic crosstalk, and support the potential for TAAR1 as a novel therapeutic target in inflammatory disorders.

Graphical Abstract

中文翻译：

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TAAR1 调节嘌呤能诱导的外周巨噬细胞（而非中枢神经系统驻留巨噬细胞）的 TNF 分泌

微量胺相关受体 1 (TAAR1) 是一种已确定的神经调节 G 蛋白偶联受体，最近的研究表明其具有与免疫调节相关的其他功能。我们的实验室之前研究了先天免疫系统细胞内的 TAAR1 表达，在此我们的目标是进一步阐明 TAAR1 在外周源性巨噬细胞和中枢神经系统驻留巨噬细胞中的功能。选择性 TAAR1 激动剂 RO5256390 与常见损伤相关分子模式（ATP 和 ADP）结合使用，观察 TAAR1 激动剂对调节细胞因子分泌和代谢谱的影响。在小鼠骨髓来源的巨噬细胞中，TAAR1 激动剂在 ATP 刺激后抑制 TNF 分泌，这似乎是代谢谱和 TNF 合成转录调节相关促炎转变的下游。相比之下，无论存在或不存在星形胶质细胞，TAAR1 激动对 ADP 诱导的小鼠小胶质细胞中 TNF 和 IL-6 的分泌没有影响。总之，我们报告了 TAAR1 与外周源性巨噬细胞（而非中枢神经系统驻留巨噬细胞）中嘌呤能信号之间的新型相互作用。这些发现提供了痕量胺能和嘌呤能串扰的第一个证据，并支持 TAAR1 作为炎症性疾病新治疗靶点的潜力。

图形概要