The role of infected and activated microglia in the pathogenesis of psychiatric disorders
Final Report Abstract
Tryptophan metabolism by the kynurenine pathway (KP) plays an important role in the pathogenesis of inflammatory, infectious, and degenerative diseases of the central nervous system (CNS). The 3-hydroxykynurenine (3-HK) branch of the KP is activated in microglia leading to the generation of 3-HK, 3-hydroxyanthranilic acid (3-HAA) and quinolinic add, that are considered neurotoxic due to their free radical-generating and NMDA receptor agonist activities. Based on these observations, KP enzymes are being actively targeted for drug development for certain neurodegenerative diseases. In the current study, we investigated the role of 3-HAA in inflammatory and antioxidant gene expression and neurotoxicity in primary human CNS cultures. Cells were stimulated with IL-1 ± IFNy or toll-like receptor (TLR) ligands in the presence or absence of 3-HAA and results were analyzed by microarray, western blot, immunostain, ELISA and neurotoxicity assays. We found that 3-HAA suppressed glial cytokine and chemokine expression and also reduced, cytokine-induced neuronal death. 3-HK was also found to protect neurons from cytokine-induced death. Unexpectedly, 3-HAA was found to be highly effective in the induction of hemoxygenase-1 (HO-1), an antioxidant enzyme with antiinflammatory and cytoprotective properties, in astrocytes but not in microglia when given alone or in concert with cytokines. Cytokines or TLR ligands by themselves did not induce HO-1 protein. Together, our results demonstrate novel species-specific activities of microglial kynurenines. They also suggest that suppression of 3-HK or 3-HAA production by inhibition of the KP enzymes might potentiate neuronal damage by changing the CNS inflammatory and redox environment.
