Inflammatory mechanisms of depression. Proinflammatory cytokines may contribute to depressive symptoms by means of various mechanisms. (1) Proinflammatory cytokines act on serotonin transporter (SERT) proteins within the brain causing a re-uptake of serotonin (5-HT) and corresponding reduced extracellular concentrations. (2) Proinflammatory cytokines up-regulate enzymes such as indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) resulting in reduced tryptophan (TRP) availability, ultimately contributing to reduced 5-HT synthesis. (3) Both 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) may contribute to elevated levels of reactive oxygen species (ROS) and oxidative stress within the brain. (4) QUIN may induce N-methyl-D-aspartate (NMDA) over-activity thereby contributing to hippocampal atrophy and a loss of glucocorticoid receptors, ultimately leading to a loss of negative feedback and hypothalamic-pituitary-adrenal (HPA) axis over-activity.