FIGURE 1.

Kynurenine pathway activation in inflammatory conditions. The enzymatic activity of the indoleamine 2,3-dioxygenase (IDO) is increased by inflammatory cytokines in activated monocytes, macrophages and brain microglia in inflammatory conditions. The essential amino acid tryptophan is therefore used for the synthesis of kynurenine, and this at the expense of the synthesis of the monoamine serotonin that directly depends on the availability of its precursor and limiting factor tryptophan. IDO activation might therefore impair serotonin neurotransmission. Kynurenine is then used to produce different neuroactive glutamatergic metabolites, including kynurenic acid, which is neuroprotective by acting on both glutamatergic NMDA and α7-nicotinic acetylcholine (α7-nAChR) receptors, and 3-hydroxykynurenine and quinolinic acid that are rather neurotoxic by promoting oxidative stress and/or activating NMDA receptors. As the activity of the kynurenine monooxygenase (KMO) that synthesizes 3-hydroxykynurenine is increased in activated microglia by inflammatory cytokines, increased production of kynurenine is ultimately associated with skewing of the kynurenine metabolic balance toward increased neurotoxicity. By impairing serotonin neurotransmission and promoting neuronal damages, cytokine-induced kynurenine pathway activation can therefore contribute to the development of inflammation-driven depressive symptoms. TrypOH, tryptophan hydroxylase; KAT, kynurenine aminotransferase; KYNU, kynureninase; 3-HAO, 3-hydroxyanthranilic acid oxygenase.