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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / drug effects
  • Animals
  • Cells, Cultured
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Gene Expression Regulation / drug effects
  • Hallucinogens / pharmacology*
  • Humans
  • Immunity, Innate / drug effects
  • Lipopolysaccharides / pharmacology
  • Methoxydimethyltryptamines / pharmacology*
  • Mice
  • Monocytes / cytology*
  • Monocytes / drug effects
  • Monocytes / immunology
  • Morpholines / pharmacology
  • N,N-Dimethyltryptamine / pharmacology*
  • Receptors, sigma / metabolism*

Substances

  • Hallucinogens
  • Lipopolysaccharides
  • Methoxydimethyltryptamines
  • Morpholines
  • Receptors, sigma
  • sigma-1 receptor
  • 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
  • N,N-Dimethyltryptamine

Grant support

This research was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 „National Excellence Program” to AS, and OTKA-NK101538 to ER. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.