Figure - PMC

Skip to main content

View full-text article in PMC

. Author manuscript; available in PMC: 2013 Jul 1.

Published in final edited form as: Nat Rev Neurosci. 2012 Jul;13(7):465–477. doi: 10.1038/nrn3257

A: In the periphery, the degradation of tryptophan and the subsequent formation of circulating kynurenines is normally regulated by steroid hormones, cytokines and growth factors. These factors stimulate IDO ^{123, 175}, and also activate, or lead to the up-regulation of, other kynurenine pathway enzymes including TDO ²⁰¹ and KMO ^{118, 132}. Jointly, they control the levels of circulating tryptophan, kynurenine and 3-HK, which all readily cross the blood-brain barrier using the large neutral amino acid transporter ⁴². Together with kynurenine pathway metabolism within glial cells, brain uptake of these kynurenines therefore determines kynurenine pathway flux in the brain; B: Inflammatory conditions stimulate the kynurenine pathway both in the periphery and in the brain. Activation of kynurenine pathway enzymes, especially IDO and KMO, in peripheral immune cells – such as dendritic cells and macrophages – promotes the production of kynurenine and its downstream metabolites in the blood. Increased influx of the brain-permeable metabolites, in some cases aided by a leaky blood-brain barrier ¹⁷³, as well as infiltration of macrophages or microbial pathogens ¹¹³, then leads to an excess of kynurenines in the brain parenchyma. Furthermore, infiltrating cytokines stimulate the kynurenine pathway in activated microglial cells and blood-borne cells within the brain ²⁰². Together, these peripheral and central events connect neuroinflammatory mechanisms with abnormal metabolism along the kynurenine pathway, and brain pathology.

A: In the periphery, the degradation of tryptophan and the subsequent formation of circulating kynurenines is normally regulated by steroid hormones, cytokines and growth factors. These factors stimulate IDO ^{123, 175}, and also activate, or lead to the up-regulation of, other kynurenine pathway enzymes including TDO ²⁰¹ and KMO ^{118, 132}. Jointly, they control the levels of circulating tryptophan, kynurenine and 3-HK, which all readily cross the blood-brain barrier using the large neutral amino acid transporter ⁴². Together with kynurenine pathway metabolism within glial cells, brain uptake of these kynurenines therefore determines kynurenine pathway flux in the brain; B: Inflammatory conditions stimulate the kynurenine pathway both in the periphery and in the brain. Activation of kynurenine pathway enzymes, especially IDO and KMO, in peripheral immune cells – such as dendritic cells and macrophages – promotes the production of kynurenine and its downstream metabolites in the blood. Increased influx of the brain-permeable metabolites, in some cases aided by a leaky blood-brain barrier ¹⁷³, as well as infiltration of macrophages or microbial pathogens ¹¹³, then leads to an excess of kynurenines in the brain parenchyma. Furthermore, infiltrating cytokines stimulate the kynurenine pathway in activated microglial cells and blood-borne cells within the brain ²⁰². Together, these peripheral and central events connect neuroinflammatory mechanisms with abnormal metabolism along the kynurenine pathway, and brain pathology.