Figure 10.

Proposed model for Kynurenine Pathway activation in the brain. Multiple studies have shown that in vivo administration of LPS or pI:C to mice increased peripheral pro-inflammatory cytokines (including IFNγ, TNFα, and IL-1β). These circulating cytokines, as well as immune cells that produce them, can enter the brain, to stimulate brain parenchymal production of additional immunomodulatory agents (cytokines and galectins). Gal-9 (produced within the brain or from the circulation) and IFNγ (from the circulation or infiltrating immune cells) synergize to increase expression of DO transcripts in the brain. Ex vivo, IFNγ is added [since brain parenchyma (i.e., OHSCs) does not express this cytokine], Gal-9 is also added to directly test its activity (but Gal-9 is expressed by cells resident to the brain). Independent of the source, IFNγ and Gal-9 increase DO expression in a DO- and transcript-specific manner, modeling in vivo responses. DO induction would increase flux down the Kynurenine Pathway to serve two purposes: supplying NAD⁺ for the brain, but with consequences (metabolites, Kyn, KynA, and QuinA, modulate behavior and immune activity).