5-HT_2Bserotonin receptor agonist BW723C86 shapes the macrophage gene profile via AhR and impairs monocyte-to-osteoclast differentiation

Abstract

word count: 249 Figures: 7 Reference count: 128 5-HT 2B shapes the macrophage transcriptome via AhR 2 KEY POINTS -The serotonin receptor 5-HT 2B modifies the human macrophage transcriptome through activation of the Aryl Hydrocarbon Receptor.-BW723C86, an agonist used for 5-HT 2B activation in vivo, exerts 5-HT 2B -independent effects and limits monocyte osteoclastogenic potential. 5-HT 2B shapes the macrophage transcriptome via AhR 3 ABSTRACT Peripheral serotonin (5-HT) exacerbates or limits inflammatory pathologies through interaction with seven types of 5-HT receptors (5-HT 1-7 ). As central regulators of inflammation, macrophages are critical targets of 5-HT, which promotes their antiinflammatory and pro-fibrotic polarization primarily via the 5-HT 7 -Protein Kinase A (PKA) axis. However, anti-inflammatory human macrophages are also characterized by the expression of 5-HT 2B , an off-target of anesthetics, anti-parkinsonian drugs and Selective Serotonin Reuptake Inhibitors (SSRI) that contributes to 5-HT-mediated pathologies. Since 5-HT 2B prevents mononuclear phagocyte degeneration in amyotrophic lateral sclerosis and modulates motility of murine microglial processes, we sought to determine the functional and transcriptional consequences of 5-HT 2B activation in human macrophages. Ligation of 5-HT 2B by the 5-HT 2B -specific agonist BW723C86, which exhibits antidepressant-and anxiolytic-like effects in animal models, significantly modified the cytokine profile and the transcriptional signature in macrophages. Importantly, 5-HT 2B agonist-induced transcriptional changes were partly mediated through activation of the Aryl hydrocarbon Receptor (AhR), a ligand-dependent transcription factor that regulates immune responses and the biological responses to xenobiotics. Besides, BW723C86 triggered transcriptional effects that could not be abrogated by 5-HT 2B antagonists and impaired monocyte-to-osteoclast differentiation by affecting the expression of negative (IRF8) and positive (PRDM1) regulators of osteoclastogenesis. Therefore, our results demonstrate the existence of a functional 5-HT 2B -AhR axis in human macrophages and indicate that the commonly used 5-HT 2B agonist BW723C86 exhibits 5-HT 2B -independent effects. The 5-HT 2B -AhR link extends the range of signaling pathways initiated upon 5-HT receptor engagement and identifies a point of convergence for endogenous and exogenous agents with ability to modulate inflammatory responses. 5-HT 2B shapes the macrophage transcriptome via AhR