Indoleamine 2,3-Dioxygenase 1/Aryl Hydrocarbon Receptor Feedback Loop Mediates Anti-inflammation in lipopolysaccharide-stimulated Astrocytes to Dampen Inflammatory Neurotoxicity.

Abstract: Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates cell immune responses in a cell type-specific and ligand-dependent manner. In the central nervous system, astrocytic AhR plays important roles in regulating neuroinflammation by mediating responses to endogenous ligands generated from the inflammation-induced indoleamine 2,3-dioxygenase 1 (IDO1)/kynurenine (KYN) pathway. We previously demonstrated that reduction of AhR expression decreases lipopolysaccharide (LPS)-induced pro-inflammatory responses in microglia. However, the role of AhR in the astrocytic immune responses and its subsequent effects on microglial activation and neurotoxicity remain unclear. In this study, we used LPS-induced neuroinflammation in rat cortical glia-neuron (GN) mix cultures, which increased the expression of tumor necrosis factor-α and interleukin-6 and microglial activation. These proinflammatory responses were attenuated by a specific AhR agonist 6-formylindolo [3,2-b] carbazole (FICZ), but not by the AhR antagonist CH223191. CH223191, which inhibits LPS- and FICZ-induced AhR activation, enhanced neurotoxicity induced by LPS-glutamate co-treatment in GN mix cultures. Furthermore, inhibition of AhR expression and activation enhanced LPS-induced proinflammatory responses, and LPS-induced AhR activation was abrogated by the inhibition of IDO1 expression in astrocytes. Notably, AhR knockdown inhibited the anti-inflammatory effects of KYN while enhancing LPS-induced IDO1 expression in astrocytes, suggesting that AhR mediates the anti-inflammatory effect of KYN and the negative feedback regulation of IDO1 expression. Finally, we examined the role of astrocytic AhR in inflammatory astrogliosis-induced neurotoxicity by treating primary cortical neurons with LPS-treated astrocyte-conditioned medium (ACM). The results revealed that ACM derived from siAhR-transfected astrocytes increased neurotoxicity. In conclusion, inflammation-activated AhR mediates the anti-inflammatory effects and negative feedback regulation of the IDO1/KYN pathway in astrocytes, thereby dampening inflammatory astrogliosis-induced neurotoxicity.