Laboratorio de Células Mieloides, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain;
Laboratorio de Células Mieloides, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain.
J Immunol. 2020 May 15;204(10):2808-2817. doi: 10.4049/jimmunol.1901531. Epub 2020 Apr 6.
Macrophages can either promote or resolve inflammatory responses, and their polarization state is modulated by peripheral serotonin (5-hydroxytryptamine [5-HT]). In fact, pro- and anti-inflammatory macrophages differ in the expression of serotonin receptors, with 5-HT and 5-HT expression restricted to M-CSF-primed monocyte-derived macrophages (M-MØ). 5-HT drives the acquisition of profibrotic and anti-inflammatory functions in M-MØ, whereas 5-HT prevents the degeneration of spinal cord mononuclear phagocytes and modulates motility of murine microglial processes. Because 5-HT mediates clinically relevant 5-HT-related pathologies (valvular heart disease, pulmonary arterial hypertension) and is an off target of anesthetics, antiparkinsonian drugs, and selective serotonin reuptake inhibitors, we sought to determine the transcriptional consequences of 5-HT engagement in human macrophages, for which 5-HT signaling remains unknown. Assessment of the effects of specific agonists and antagonist revealed that 5-HT engagement modifies the cytokine and gene signature of anti-inflammatory M-MØ, upregulates the expression of aryl hydrocarbon receptor (AhR) target genes, and stimulates the transcriptional activation of AhR. Moreover, we found that 5-HT dose dependently upregulates the expression of AhR target genes in M-MØ and that the 5-HT-mediated activation of AhR is 5-HT dependent because it is abrogated by the 5-HT-specific antagonist SB204741. Altogether, our results demonstrate the existence of a functional 5-HT/5-HT/AhR axis in human macrophages and indicate that 5-HT potentiates the activity of a transcription factor (AhR) that regulates immune responses and the biological responses to xenobiotics.
巨噬细胞可以促进或解决炎症反应，其极化状态受外周血清素（5-羟色胺[5-HT]）调节。事实上，促炎和抗炎巨噬细胞在 5-HT 受体的表达上存在差异，5-HT 和 5-HT 表达仅限于 M-CSF 诱导的单核细胞来源的巨噬细胞（M-MØ）。5-HT 驱动 M-MØ 获得促纤维化和抗炎功能，而 5-HT 可防止脊髓单核吞噬细胞变性，并调节小鼠小胶质细胞过程的运动。由于 5-HT 介导临床上相关的 5-HT 相关病理（心脏瓣膜病、肺动脉高压），并且是麻醉剂、抗帕金森病药物和选择性 5-羟色胺再摄取抑制剂的脱靶，我们试图确定 5-HT 在人类巨噬细胞中的作用的转录后果，因为 5-HT 信号在人类巨噬细胞中仍然未知。评估特定激动剂和拮抗剂的作用发现，5-HT 结合可改变抗炎 M-MØ 的细胞因子和基因特征，上调芳烃受体（AhR）靶基因的表达，并刺激 AhR 的转录激活。此外，我们发现 5-HT 以剂量依赖的方式上调 M-MØ 中 AhR 靶基因的表达，并且 5-HT 介导的 AhR 激活是 5-HT 依赖性的，因为它被 5-HT 特异性拮抗剂 SB204741 阻断。总的来说，我们的结果证明了人类巨噬细胞中存在功能性 5-HT/5-HT/AhR 轴，并表明 5-HT 增强了调节免疫反应和对外源生物反应的转录因子（AhR）的活性。
