PLoS One. 2014 Aug 29;9(8):e106533. doi: 10.1371/journal.pone.0106533.

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

Attila Szabo1,2, Attila Kovacs3, Ede Frecska3, Eva Rajnavolgyi1,2

1Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

2Research Centre for Molecular Medicine, University of Debrecen, Debrecen, Hungary

3Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

 

Abstract

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. 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. 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.

PMID: 25171370

 

SUPPLEMENTS:

In neuropsychiatric research it is an increasingly accepted hypothesis that a number of diseases affecting large populations (such as Alzheimer’s, Parkinson’s disease, Major depression) are caused by the chronic inflammation of the central nervous system. High-resolution whole genome-wide association studies found significant correlations between the gene polymorphisms of innate immune receptors and the frequency of late onset Alzheimer’s disease (AD). It has also been demonstrated by several groups that in mice the specific activation of the mother’s Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) by polyI:C and LPS results in decreased neurogenesis, cognitive deficits, and a marked increase in the appearance and deposition fo Aβ aggregates in the brain of the offspring. The orphan receptor sigma-1 has been shown to mediate anti-inflammatory responses in rodents in vivo, however, the background of this phenomenon is yet to be clarified. Furthermore, monocyte-derived dendritic cells (moDCs) and macrophages were reported to accumulate in the brain tissue under chronic inflammatory conditions.

In this study, we used two endogenous (NN-DMT and 5-MeO-DMT) and a high affinity synthetic ligand (PRE-084 hydrochloride) to trigger sigma-1 receptor in human moDCs and examined their effect on the LPS/polyI:C-induced inflammatory responses elicited by moDCs. We found that co-administration of sigma-1 ligands with LPS or polyI:C significantly inhibited the production of inflammatory cytokines and chemokines (IL-1β, IL-6, TNFα, IL-8), while markedly increased the secretion of the anti-inflammatory IL-10. Moreover, this effect was also observed in case of antigen-presenting capacity of moDCs. Co-administration of sigma-1 ligands with E. coli or inactivated influenza virus significantly decreased the number of primed autologous naive Th1 and Th17 cells involved inflammatory adaptive immune responses. The role of sigma-1 in these processes was confirmed with gene-silencing. In conclusion, our results show that specific activation of the sigma-1 receptor in moDCs effectively inhibit innate and adaptive inflammatory responses (Figure 1.). Targeting of the sigma-1 receptor in brain-resident moDCs may be a promising pharmacological strategy in cases of AD and other chronic inflammatory conditions of the CNS.

 

Figure 1_WBF short summary_AS

Figure 1. Pharmacological modulation of APC and lymphocyte cytokine signaling by sigma-1 receptor ligands

Psychotropic tryptamines can significantly interfere with immune cell cytokine profiles. This may lead to suppression of antigen-presentation and inflammatory cytokine and chemokine secretion, as well as inhibition of isotype switching or elevated levels of anti-inflammatory cytokines in the tissue environment. Arrows represent activation or migration of cells, or secretion of cytokines. T-arrows mean inhibition. Abbreviations: DMT: N,N-dimethyltryptamine; 5-MeO-DMT: 5-methoxy-N,N-dimethyltryptamine; PRE-084: a synthetic, high affinity sigma-1 receptor ligand; Mo: monocyte; DC: dendritic cell; MФ: macrophage; colored halos around cells represent activation/cytokine secretion.

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