Neuroimmune signaling: a key component of alcohol abuse.

Summary diagram of TLR4 signaling cascadeTLRs signal as dimers and heterodimers that recruit adaptor proteins such as CD14 and MD2. Depending on the adaptors recruited by the activated TLR, different pathways can be triggered, all of which culminate in activation of the pro-inflammatory transcription factor NF-κB. One pathway involves MyD88 and TIRAP and results in activation of NF-κB via IκB kinase. Another pathway uses NADPH oxidase that can activate NF-κB through ROS. TRIF and TRAM signaling proteins also initiate signal cascades, culminating in the activation of NF-κB and other pro-inflammatory transcription factors. RAGE is another transmembrane receptor operating in innate immune cells that is known to respond to HMGB1, and this pathway also induces pro-inflammatory gene transcription via NF-κB activation. The release of cytokines such as TNF-α, HMGB1, IL-1β, chemokines, proteases, and ROS activate adjacent cells. These cytokines affect the brain and are thought to contribute to the etiology, progression, and persistence of alcohol addiction. “Off-the-shelf” FDA-approved drugs (shown here in boxes along with their site of action) are anti-inflammatory and interfere with the TLR4 signaling cascade. These examples are discussed in the text and represented here because they have been shown to decrease alcohol consumption and modify other alcohol behaviors. Bold red font indicates a gene that has been manipulated and shown to affect ethanol-related behavior.NF-κB: Nuclear factor κ light-chain-enhancer of activated B cellsMyD88: Myeloid differentiation primary response gene 88TIRAP: Toll-interleukin 1 receptor (TIR) domain containing adaptor proteinROS: Reactive oxygen speciesTRIF: TIR-domain-containing adaptor-inducing IFNβTRAM: Trif-related adaptor moleculeRAGE: Receptor for advanced glycation endproductsTNF-α: Tumor necrosis factor-αIL-1β: Interleukin-1 beta

Gut-brain axis and alcohol dependenceLipopolysaccharide (LPS), a gram-negative bacterial endotoxin, is normally localized to the gut. Ethanol jeopardizes the tight junctions of the intestinal mucosa allowing LPS to enter systemic circulation. Once in the bloodstream, LPS binds to TLR4 receptors on liver macrophages, Kupffer, and stellate cells and activates signaling cascades that result in an increase of pro-inflammatory genes (cytokines, chemokines, proteases, ROS) via activation of the transcription factor NF-κB. This process is known to be a key factor in the development of alcoholic liver disease. These cytokines then enter the bloodstream, cross the BBB, and activate microglia, the brain’s resident macrophages. Microglial activation increases the expression of pro-inflammatory genes in the brain which is hypothesized to increase alcohol consumption behavior.