Here, we report that acute TLR3 agonist, poly I:C, systemic administration increases blood and brain TNFα, IL-1 β, IL-6, and MCP-1. Brain responses persist for at least three days, whereas blood levels return to controls by one day. Chronic ethanol treatment causes mild increases in blood and brain, whereas sequential ethanol-poly I:C treatment leads to large responses, with increases in blood and brain proinflammatory responses across treatment groups. Increased levels of brain cytokines coincided with activated microglial morphology, increased NOX gp91phox, superoxide and markers of neuronal cell death, for example, activated caspase-3 and Fluoro-Jade B staining. Ethanol potentiation of poly I:C was associated with ethanol-induced TLR3 and HMGB1 expression. Blocked microglial activation by minocycline and naltrexone blunted cell death markers. These studies suggest that the magnitude of systemic proinflammatory responses contribute to the magnitude of microglial activation, brain neuroinflammation and neurodegeneration.
