Abstract
Serotonin is a monoamine neurotransmitter that signals through a wide array of receptors (5-HT1–7) many of which are also involved in immune processes. Dendritic cells (DCs) are crucial players in immune defense by bridging innate and adaptive immune responses via their vast repertoire of pattern recognition receptors and antigen-presenting capability. Although serotonin is known to influence immunity at many levels, cell type-specific expression and function of its receptors remains poorly understood. Here we aimed to study 5-HT1–7 expression and function in CD1a− and CD1a+ human monocyte-derived DCs (moDCs). We found that the 5-HT2B receptor-subtype is solely expressed by the inflammatory CD1a+ moDC subset. Specific 5-HT2B activation potently inhibited TLR2, TLR3, and TLR7/8-induced proinflammatory cytokine and chemokine (TNF-α, IL-6, IL-8, IP-10, IL-12) but not type I interferon-β responses. 5-HT2B agonism also interfered with the polarization of CD1a+ moDC-primed CD4+ T cells towards inflammatory Th1 and Th17 effector lymphocytes. Here we report the subset-specific expression and immunomodulatory function of 5-HT2B in human moDCs. Our results expand the biological role of 5-HT2B which may act not only as a neurotransmitter receptor, but also as an important modulator of both innate and adaptive immune responses.
Highlights
Dendritic cells (DCs) represent a diverse population of myeloid cells in higher vertebrates which play a crucial role in bridging innate and adaptive immunity in multiple tissue types
In line with these findings, the protein level of 5-HT2B increased significantly in CD1a+ cells after activation by polycytidylic acid (polyI):C, we found no detectable levels of the receptor in CD1a− cells either at baseline or post-activation as measured by western blot (Fig. 1C,D)
This suggests a subset-specific expression of 5-HT2B in human monocyte-derived dendritic cells
Summary
Dendritic cells (DCs) represent a diverse population of myeloid cells in higher vertebrates which play a crucial role in bridging innate and adaptive immunity in multiple tissue types They fine-tune and control immune responses ensuring the maintenance of self tolerance as well as modulating lymphocyte functions by priming naive T cells and thereby contributing to the establishment of effector and memory subsets. The ligation of PRRs usually leads to DC activation triggering the release of cytokines and chemokines, a phenomenon which is highly dependent on the nature of the stimulus, the surrounding tissue microenvironment and the participating PRR or cross-talk of PRRs, such as Toll-like receptors (TLRs) or RIG-I-like receptors (RLRs)[2] This event leads to acute inflammatory and/or interferon responses through the mobilization of downstream signaling by nuclear factor kappa-B (NF-κB) and interferon regulatory factors (IRFs), respectively. Our major goal was to test the hypothesis that specific 5-HT receptor ligation can interfere with inflammatory reponses in this DC subset, which may as well expand our knowledge in the physiology and neuroimmunology of serotonin
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