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.
Highlights
The term sigma receptor dates back historically to the sigma/ opioid receptor described by Martin et al [1] and reported to mediate the psychotropic effects of N-allylnormetazocine (NANM)
We first sought to monitor the expression of sigmar-1 in human primary myeloid cells (Figure 1) and found that sigmar-1 was expressed in primary human blood monocytes and its expression increased during the differentiation process toward macrophages and monocyte-derived DCs (moDCs) shown by the increasing levels of sigmar-1 protein in both monocyte-derived macrophages and moDCs (Figure 1A and 1B)
Since the expression and function of sigmar-1 has already been established in macrophages, and moDCs showed comparable levels of sigmar-1 to monocyte-derived macrophages (moMACs), in our further studies we focused on moDCs
Summary
The term sigma receptor dates back historically to the sigma/ opioid receptor described by Martin et al [1] and reported to mediate the psychotropic effects of N-allylnormetazocine (NANM). Studies showed that sigmar-1 is expressed in distinct regions of the CNS and in immune cells [4,6]. Sigma-1 receptor ligands possess potent immunoregulatory properties via increasing the secretion level of anti-inflammatory IL-10 [11], and suppressing IFNc and GM-CSF expression [10]. These important studies showed that sigmar-1 may cause significant alterations in immune functions
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