**2.7. The brain and immune responses**

The interface between the brain and the immune system is bidirectional. Recent findings have revealed that alcohol causes the release of HMGB1 in the gut, which in turn activates TLR4

**Figure 3.** Alcohol-induced elevation of TGF-β1 levels in neuronal cells is accompanied by a host of molecular and chemical changes related to cell death.

**Figure 4.** Alcohol influences neuroimmune signaling via its effects on the gut.

resulting in an increased gut permeability. As a result, there is activation of proinflammatory cytokines in the liver, which leads to induction of TNF-α and other cytokines in the blood. Researchers found that LPS induced increases in serum TNF-α as well as proinflammatory cytokines, leading to induction of the gene in the brain [77]. This proinflammatory cytokines in the blood are then transported across the blood–brain barrier (BBB) by their receptors [78]. For example, 2 to 3 g/kg ethanol when administered into the stomach results in the activation of innate immune response in the gut [79]. This damages the tight junction present in the gut resulting in an opening of the sites where gut bacteria and their endotoxins (LPS) can easily enter the blood stream leading to the liver, where they can activate proinflammatory cytokines (**Figure 4**). Increased proinflammatory cytokines responses, which affects the brain through TNF-α and other cytokines [80]. The brain response to the proinflammatory cytokine MCP-1 is quite longer than that found in the liver and blood [81]. An in vivo study showed an increased LPS induction of proinflammatory cytokines (TNF-α, IL-1β and MCP-1) only in the brain but not in the liver and blood after ten daily doses of alcohol [81]. In the liver, the researcher suggested that the anti-inflammatory cytokine (IL-10) inhibits NF-κB which was increased after 1 week of ethanol treatment but decreased in the brain [81]. After 10 days of ethanol (5g/kg/day) administration to mice model, this study showed sensitization to TLR3 agonist Poly:IC which induces proinflammatory cytokines in the brain for 24 hours [74].
