Journal
JOURNAL OF IMMUNOLOGY
Volume 204, Issue 10, Pages 2808-2817Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1901531
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Funding
- Ministerio de Ciencia e Innovacion [SAF2014-52423-R, SAF2017-83785-R]
- Fundacio La Marato/TV3 [201619.31]
- Red de Investigacion en Enfermedades Reumaticas [RD16/0012/0007]
- European Regional Development Fund A way to achieve Europe
- Formacion de Personal Investigador predoctoral fellowship from Ministerio de Ciencia e Innovacion [BES-2009-021465, BES-2015-071337]
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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-HT(7 )expression restricted to M-CSF-primed monocyte-derived macrophages M-Mempty set, whereas 5-HT(7 )drives the acquisition of profibrotic and anti-inflammatory functions in M-Mempty set, 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-Mempty set, 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-Mempty set 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.
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