5-Hydroxytryptamine Modulates Migration, Cytokine and Chemokine Release and T-Cell Priming Capacity of Dendritic Cells In Vitro and In Vivo

Tobias Müller,Sanja Cicko,Yared Herouy,Melanie Grimm,Francesco Di Virgilio,Stephan Sorichter,Davide Ferrari,Marco Idzko,Thorsten Dürk,Britta Blumenthal,Johannes Norgauer,Elisabeth Panther,Stefan Bereswill

doi:10.1371/journal.pone.0006453

Tobias Müller, Sanja Cicko + Show 11 more

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https://doi.org/10.1371/journal.pone.0006453

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Abstract

Beside its well described role in the central and peripheral nervous system 5-hydroxytryptamine (5-HT), commonly known as serotonin, is also a potent immuno-modulator. Serotoninergic receptors (5-HTR) are expressed by a broad range of inflammatory cell types, including dendritic cells (DCs). In this study, we aimed to further characterize the immuno-biological properties of serotoninergic receptors on human monocyte-derived DCs. 5-HT was able to induce oriented migration in immature but not in LPS-matured DCs via activation of 5-HTR1 and 5-HTR2 receptor subtypes. Accordingly, 5-HT also increased migration of pulmonary DCs to draining lymph nodes in vivo. By binding to 5-HTR3, 5-HTR4 and 5-HTR7 receptors, 5-HT up-regulated production of the pro-inflammatory cytokine IL-6. Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs. Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype. Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo. In summary, our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders.

Highlights

Outside the central nervous systems 5-hydroxytryptamine (5HT), commonly known as serotonin, is found mainly in platelets and can be released during platelet aggregation
Our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders
We demonstrated that 5-HT is a chemoattractant for immature but not LPS-matured dendritic cells (DCs) in vitro and in vivo, via activation of 5-HTR1B and 5HTR2 subtypes, while it modulate the secretion of IL-6, CXCL10, CCL22 and the T-cell polarization capacity of mature DC, via activation of 5-HTR4 and 5-HTR7 subtypes

Summary

Introduction

Outside the central nervous systems 5-hydroxytryptamine (5HT), commonly known as serotonin, is found mainly in platelets and can be released during platelet aggregation. Apart from its well-characterized function as a neurotransmitter, 5-HT has been reported to be a potent immunoregulator: Stimulation of serotoninergic receptors in human monocytes or lung epithelial cells is associated with secretion of pro-inflammatory cytokines [13,14]. We were able to demonstrate the functional expression of 5-HTR on human DCs, linked to intracellular Ca2+signalling and cytokine secretion [25]. We demonstrated that 5-HT is a chemoattractant for immature but not LPS-matured DC in vitro and in vivo, via activation of 5-HTR1B and 5HTR2 subtypes, while it modulate the secretion of IL-6, CXCL10, CCL22 and the T-cell polarization capacity of mature DC, via activation of 5-HTR4 and 5-HTR7 subtypes

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