Polyinosinic Polycytidylic Acid (poly I:C) Induces Neuronal Cell Death Through NF-κB-Mediated Inflammation in Human Microglia and Neuroinflammation-Induced Cognitive Impairment in Mice

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Neuroinflammation and neuronal death are direct consequences of persistent microglial activation, a phenomenon observed in many chronic neurological conditions. Activated microglia impact neuronal cells by releasing proinflammatory cytokines and inflammatory mediators, leading to neuronal damage and neurodegeneration. To investigate whether polyinosinic polycytidylic acid (poly I:C), a synthetic double-stranded RNA molecule, induces neuroinflammation and neuronal death, we exposed human microglia (HMC-3 cells) to poly I:C for 24 h, and performed inflammatory cytokine analysis. Additionally, to investigate whether poly (I:C) induces memory impairment and motor coordination deficits in mice, we conducted a behavioral assessment and also measured the expression of inflammatory cytokines in the brain. Poly (I:C) exposure significantly increased the mRNA and protein expression of inflammasome, proinflammatory cytokines (TNFα, IL-6, IL-1β, IL-8, IL-12, and IL-18) and chemokines in microglia. Poly (I:C) also significantly increased the translocation of NF-kB from the cytosol to the nucleus. Furthermore, the conditioned medium from poly (I:C)-treated cells markedly increased apoptosis in human neuronal cells (differentiated SHSY5Y cells) by activating pro-apoptotic markers, including Bax, Bad, cleaved caspase-3, cleaved PARP, and AIF. Mice exposed to poly (I:C) showed a significant increase in mRNA expression of inflammatory cytokines, such as IL-6 and TNF-α, in the hippocampus. A decrease in the percentage of alternation on the T-maze, reduced distance travelled, and average speed in the open field test indicate cognitive deficits as well as anxiety-like behavior in mice exposed to poly (I:C). These findings suggest that poly (I:C) induces neuroinflammation through the inflammasome and proinflammatory mediators via the NLRP3/NF-κB signaling pathway in vitro and in vivo.
Funding Information
  • National Institute of Neurological Disorders and Stroke (R01NS112642)

This publication has 41 references indexed in Scilit: