Serotonin (5-HT) Shapes the Macrophage Gene Profile through the 5-HT 2B-Dependent Activation of the Aryl Hydrocarbon Receptor

J Immunol. 2020 May 15;204(10):2808-2817. doi: 10.4049/jimmunol.1901531. Epub 2020 Apr 6.

Abstract

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-HT2B and 5-HT7 expression restricted to M-CSF-primed monocyte-derived macrophages (M-MØ). 5-HT7 drives the acquisition of profibrotic and anti-inflammatory functions in M-MØ, whereas 5-HT2B prevents the degeneration of spinal cord mononuclear phagocytes and modulates motility of murine microglial processes. Because 5-HT2B 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-HT2B engagement in human macrophages, for which 5-HT2B signaling remains unknown. Assessment of the effects of specific agonists and antagonist revealed that 5-HT2B 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-HT2B dependent because it is abrogated by the 5-HT2B-specific antagonist SB204741. Altogether, our results demonstrate the existence of a functional 5-HT/5-HT2B/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cells, Cultured
  • Humans
  • Indoles / pharmacology
  • Macrophages / physiology*
  • Microglia / physiology*
  • Phagocytosis
  • RNA, Small Interfering / genetics
  • Receptor, Serotonin, 5-HT2B / metabolism*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / pharmacology
  • Signal Transduction
  • Thiophenes / pharmacology
  • Transcriptional Activation
  • Transcriptome

Substances

  • 1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine
  • Indoles
  • RNA, Small Interfering
  • Receptor, Serotonin, 5-HT2B
  • Receptors, Aryl Hydrocarbon
  • Receptors, Serotonin
  • Serotonin 5-HT2 Receptor Agonists
  • Thiophenes
  • serotonin 7 receptor
  • Serotonin