Figure 2.

IDO and the kynurenine pathway in inflammation-induced CNS pathology. Cytokine-induced activation of IDO in peripheral immune cells (eg, macrophages and dendritic cells) or cells in the brain (eg, microglia, astrocytes, and neurons) leads to the production of kynurenine, which is converted to KA by KAT-II in astrocytes or quinolinic acid by kynurenine-3-monooxygenase (KMO) and 3-hydroxy-anthranilic acid oxygenase (3-HAO) in microglia or infiltrating macrophages. Through blockade of the α7nAChR, KA can reduce glutamate release as well as the release of dopamine, both of which can contribute to cognitive dysfunction. By contrast, quinolinic acid through activation of the NMDA receptor can increase glutamate release as well as lead to lipid peroxidation, thus contributing to excitotoxicity, oxidative stress, and ultimately neurodegeneration.