Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells
This in vitro (neuronal cell culture) study investigated the anti-inflammatory effects of NN-DMT and 5-MeO-DMT (100 μM), and demonstrate that its immunomodulatory effects on the functional activities of human dendritic cells operate through the sigma-1 receptor.
Authors
- Attila Szabo
- Ede Ottó Frecska
Published
Abstract
Introduction
The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models.
Methods
Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses.
Results
Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.
Research Summary of 'Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells'
Introduction
Sigma-1 (sigmar-1) is an endoplasmic reticulum–associated chaperone receptor expressed in the central nervous system and in immune cells, and earlier studies in rodents implicated it in cell survival, neuronal differentiation and immunosuppression. Previous work has shown that sigmar-1 ligation can increase anti-inflammatory IL-10 and suppress pro-inflammatory mediators in vivo, and that endogenous indole alkaloids such as N,N-dimethyltryptamine (NN-DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) bind sigmar-1. However, the role of sigmar-1 and its endogenous ligands in human myeloid immune cells, particularly monocyte-derived dendritic cells (moDCs), had not been characterised. Szabo and colleagues set out to determine whether NN-DMT and 5-MeO-DMT modulate inflammatory responses of human primary moDCs via the sigma-1 receptor. The study tested effects on innate cytokine responses to Toll-like and RIG-I–like receptor agonists and on subsequent moDC-driven CD4+ T-cell polarisation, and used gene-silencing and a selective sigmar-1 agonist to probe receptor dependence. The broader aim was to evaluate whether DMT–sigmar-1 signalling could represent a regulatory axis relevant to chronic inflammatory and autoimmune conditions affecting the CNS and peripheral tissues.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Szabo, A., Kovacs, A., Frecska, E., & Rajnavolgyi, E. (2014). Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells. PLoS ONE, 9(8), e106533. https://doi.org/10.1371/journal.pone.0106533
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