It is not clear why signaling through TLR4 but not via other cytokine receptors seems to contribute significantly to ethanol responses, because all of these receptors generally belong to the same receptor superfamily (i.e., the TLR–IL1-R superfamily) (Wald et al. 2003) and share kinase cascades in monocytes and microglia that all converge upon NF-κB. The findings suggest that the TLR4s on neurons or other brain cells may have some unique properties that differ from NF-κB activation by receptors for TNF-α, IL-1β, and other cytokines (e.g., TNF receptor) which induce NF-κB transcription of proinflammatory cytokines. Further complicating the picture, the TLR4 signaling pathway is not the only one affected by ethanol exposure. Vetreno and colleagues (2013) found that chronic intermittent treatment of adolescent rats also led to persistent increases in the expression of another receptor stimulated by HMGB1, called receptor for advanced glycation end products (RAGE) (see figure 1). Although the mechanisms remain complicated, together these studies suggest that HMGB1–TLR4 and perhaps RAGE signaling (which are found on multiple brain cells types) as well as neuronal–glial neuroimmune signaling and microglial–astrocyte activation all contribute to alcohol-induced brain damage.
