Tryptamine treatment results in the amelioration of EAE by inducing an anti-inflammatory shift in the Th17/Treg balance mediated by regulation of miRNA expression profile

Abstract

Abstract In this study we focus on understanding the novel immunotherapeutic potential of tryptamine, a bioactive indole compound derived from microorganisms and various botanicals, in the context of ameliorating symptoms of Experimental Autoimmune Encephalomyelitis (EAE). EAE is used in the laboratory setting to replicate the etiology as well as pathology of Multiple Sclerosis (MS) in murine organisms for research purposes. Globally MS, an incurable autoimmune disorder, is experiencing increases in incidence and treatment costs which places emphasis on the discovery of novel immunosuppressents with limited toxicity. In this study we show that tryptamine poses potent immunosuppressive activity and ameliorates the clinical parameters of EAE by shifting the balance of CD4+ T cells from a pro-inflammatory T helper 17 cell (Th17) towards an anti-inflammatory T regulatory cell (Treg) dominated landscape in chronic progressive EAE. Based on preliminary miRNA array data, we have found that the observed shift in the Th17/Treg balance following tryptamine treatment is due to an anti-inflammatory miRNA expression profile within the lymphocytes of treated mice. MiR-3473g and miR-140-3p, putative targets of the enzyme SIRT1, were found to be upregulated within the lymphocytes of tryptamine treated mice. SIRT1 in the context of inflammatory disorders works as a marker of pro-inflammatory responses in lymphocytes due to SIRT1’s activation of the master transcription factor of Th17 cells known as RORγt. This epigenetic regulation of gene expression provides a clearly linkable mechanism explaining the shift in the Th17/Treg balance as well as the amelioration of symptoms observed following tryptamine treatment in EAE mice.