Figure 13

Schematic summary and hypothetical mechanisms of neuroinflammation and neurodegeneration. (Lower left) Chronic ethanol treatment potentiates poly I:C increases serum TNFα IL-1β, IL-6 and MCP-1 protein. These proteins in the blood enter the brain through transport systems or other mechanisms as described in the discussion (upper left). In brain these proinflammatory cytokines activate microglia. Ethanol can also directly activate NF-κB transcription. Activated microglia amplify the brain neuroinflammatory response through at least three potential mechanisms. Loop 1 represents microglial synthesis and release of cytokines that activate transcription factor NF-κB to synthesize and release more inflammatory cytokines, which further activates the microglia, producing more proinflammatory signals. Loop 2 involves activation of NADPH oxidase (NOX) in microglia that produces reactive oxygen species that activate transcription factor NF-κB to synthesize and release more inflammatory cytokines. Loop 3 involves HMGB1, a TLR activator, and TLR3 on microglia that stimulates NF-κB and microglial activation. Cytokine, glutamate and/or ethanol release of HMGB1 that can activate multiple TLR receptors on microglia. Our findings of ethanol increased HMGB1 and TLR3 expression in brain support a role for loop 3 in microglial activation. Together, these amplify proinflammatory responses that spread from microglia to neurons (upper right). Neuronal expression of NOX increases oxidative stress leading to neuronal death. Minocycline and naltrexone block microglial activation and blunt neuronal death. These studies suggest that blood proinflammatory signals contribute to neuroinflammation and neurodegeneration that can be prevented by blocking microglial proinflammatory activation