title: 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.
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.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Research Centre for Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Szabo
authors.affiliation: Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.affiliation: Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Ede
authors.initials: E
authors.lastname: Frecska
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Research Centre for Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Eva
authors.initials: E
authors.lastname: Rajnavolgyi
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006213:Hallucinogens / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008732:Methoxydimethyltryptamines / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D009025:Morpholines / Q000494:pharmacology; D004130:N,N-Dimethyltryptamine / Q000494:pharmacology*; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D006213:Hallucinogens; D008070:Lipopolysaccharides; D008732:Methoxydimethyltryptamines; D009025:Morpholines; D004130:N,N-Dimethyltryptamine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate