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Significance Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunoregulatory enzyme that transforms tryptophan into kynurenine, an endogenous agonist of the aryl hydrocarbon receptor (AhR) whose activation sustains IDO1 expression and activity over the long term in dendritic cells (DCs). Here we found thatN -acetylserotonin (NAS), a tryptophan metabolite produced along the serotonin pathway, acts as a positive allosteric modulator (PAM) of IDO1 and thus increases kynurenine-mediated AhR activation in DCs. NAS effects on IDO1 translated into protection of mice from neuroinflammation and reinstallment of physiologic IDO1 activity in peripheral blood mononuclear cells from patients with relapsing-remitting multiple sclerosis.

Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation