Title : The kynurenine pathway in brain cells and its involvement in neuroinflammatory diseases
The kynurenine pathway (KP) of tryptophan metabolism is one of the major regulatory mechanisms of the immune response. Activation of the KP is implicated in the pathogenesis of a wide range of neuro inflammatory diseases. Several pro-inflammatory mediators can activate indoleamine 2,3 dioxygenase (IDO-1) one of the first and regulatory enzymes of the KP. A prolonged activation of the KP leads to production and accumulation of several neuroactive metabolites including the potent excitotoxin quinolinic acid (QUIN). Every brain cell types appear to express differently the KP enzymes and producing different KP metabolites. Neurons, astrocytes, oligodendrocytes and brain microvascular endothelial cells produce neuroprotective compounds whereas activated microglia, pericytes, and infiltrating macrophages synthesize and release neurotoxic KP metabolites. Tumours use the KP to switch off the immune response and produce energy for proliferation. We have shown that the KP is activated and QUIN level in most of the major neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis…), brain cancers (glioblastoma, neuroblastoma…) and neuropsychiatric disorders (depression, suicidality, schizophrenia, autism…). This dynamic and complex interplay between KP metabolites from different brain and immune cells is directly involved in the global and progressive inflammatory response involved in the neuro pathogenesis of major brain diseases and tumours.