β-catenin negatively regulates IL-6 and IL-8 expression at transcriptional level and induces reactivity in human astrocytes

Abstract

Abstract HIV invades the brain during acute infection, setting the stage for persistent neuroinflammation despite combined antiretroviral therapy (cART) and leads to HIV-Associated Neurocognitive Disorders (HAND), which occurs in ~50% of HIV-infected individuals. Our lab is focused on understanding the role of Wnt/β-catenin signaling in HAND. Here, we evaluated the impact of β-catenin on inflammatory mediators associated with neuroinflammation, chemotactic molecules, and regulation of A1 (proinflammatory)/A2 (protective/repair) phenotypes of astrocytes. We demonstrate that knockdown (KD) of β-catenin in normal human astrocytes (NHAs) significantly induced IL-6 and IL-8 at the transcription and protein levels and conversely, induction of β-catenin significantly downregulated these two molecules. These findings are intriguing given that no role for β-catenin to date is associated with IL-6 and IL-8 regulation. Further, KD of β-catenin induced three genes associated with A1 phenotype by 2.4–6.4 fold. These findings indicate that β-catenin expression in astrocytes is a critical regulator of anti-inflammatory responses and its disruption can potentially mediate persistent neuroinflammation.