Early Effects of Poly(I:C)-induced Neuroinflammation on Hippocampal Astrocyte Function and Glycolytic Metabolism

Concern is growing about the role of neurotropic viruses, such as Zika virus, West Nile virus, herpes simplex virus, SARS-CoV-2, and human immunodeficiency virus, in central nervous system (CNS) infections, which trigger host immune responses, neuronal dysfunction and brain injury. Astrocytes function as immune system cells and, together with microglia, participate in the activation and maintenance of neuroinflammatory responses, a common pathophysiological event in neurodegenerative diseases. The reactive phenotype of glial cells leads to the synthesis and release of inflammatory mediators inducing a neurometabolic shift to nonoxidative glycolysis, a phenomenon similar to the Warburg effect. However, since viruses require energy from host cells to replicate, it is essential to understand the increase in glucose consumption during viral infections. For this purpose, we used an early polyinosinic:polycytidylic acid [Poly(I:C)] induced neuroinflammation model to investigate its effects on astrocyte function and neurometabolic responses in two approaches: acute hippocampal slices and in vivo intraperitoneal administration from male Wistar rats (PN30). We evaluated the effects of a dose–response curve of Poly(I:C), an immunostimulant agent that mimics double-stranded RNA virus infection, on the neuroinflammatory response, astrocyte reactivity, and glycolytic parameters. Poly(I:C) induced neuroinflammation and astrocyte reactivity in a dose-dependent manner. Both models of Poly(I:C)-induced early neuroinflammation and astrocyte reactivity which leads to neurometabolic reprogramming with enhanced several glycolytic parameters, such as glucose uptake and hexokinase activity, methylglyoxal (MG) synthesis and affect the glyoxalase-1 (GLO1) activity. Accordingly, inflammatory and glycolytic inhibitors reduced the glycolytic parameters induced by Poly(I:C). As expected, the inflammatory inhibitors downmodulated neuroinflammatory parameters, with arundic acid in particular reversing astrocyte reactivity. Moreover, the downregulation of the glycolytic pathway had a greater effect on the pronounced inflammatory process, and reversed the astrocyte reactivity induced by Poly(I:C) neuroinflammation. Our data are consistent with the hypothesis that a metabolic shift is required to maintain neuroinflammatory signaling, particularly in early Poly(I:C) induced neroinflammation, and highlight the glycolytic pathway as a potential target for controlling the neuroinflammatory response.