Ethanol intake enhances inflammatory mediators in brain: role of glial cells and TLR4/IL-1RI receptors

Abstract

The brain is one of the major target organs of ethanol actions, and its chronic and acute intoxication results in significant alterations in brain structure and function, and in some cases to neurodegeneration. Glial cells and Toll-like receptors (TLRs) are vital players in CNS immune response; dysregulation of this response plays an important role in brain damage and neurodegeneration. Ethanol has immunomodulatory effects and induces specific alterations in the TLRs response in many tissues. These actions depend on the cell type, ethanol dose and treatment duration, as well as the concomitant presence of pathogens and their characteristics. Recent findings indicate that low concentrations of ethanol (10 mM) promote inflammatory processes in brain and in glial cells by up-regulating cytokines and inflammatory mediators (iNOS, NO, COX-2), and by activating signaling pathways (IKK, MAPKs) and transcriptional factors (NF-kappaB, AP-1) implicated in inflammatory injury. TLR4/IL-1RI receptors may be involved in ethanol-mediated inflammatory signaling, since blocking these receptors abolishes the production of ethanol-induced inflammatory mediators and cell death. We propose that at low physiologically relevant concentrations, ethanol facilitates TLR4/IL-1RI recruitment into lipid rafts microdomains, leading to the activation and signaling of these receptors. In summary, current results suggest that TLR4/ IL-1RI are important targets of ethanol-induced inflammatory brain damage.

Critical Role of TLR4 Response in the Activation of Microglia Induced by Ethanol

“…Although the differential effects of ethanol on the immune system are not well understood, it has been suggested that alcohol could modulate both the early and late steps of the TLR4-mediated activation (67). We proposed that ethanol, by interacting with the membrane microdomain lipid rafts, can activate or inhibit the TLR4 response (22). In accord with this proposal, we have demonstrated that either ethanol (at low/moderate concentrations) or LPS is capable of inducing translocation and clustering of TLR4 and signaling molecules (IRAK, MyD88, ERK) into isolated lipid rafts (24,42).…”

“…inflammatory mediators and induces neural cell death (21). Although the molecular events from CNS injury leading to the activation of innate immunity are not well understood, we have proposed that ethanol activates IL-1RI/TLR4 receptors in glial cells and triggers neuroinflammation, which contributes to the pathogenesis of brain damage induced by ethanol consumption (22). However, whether microglia activation contributes to these events is presently unknown.…”

“…These findings provide insight into the basic mechanisms participating in ethanol-induced neuroinflammation and brain damage (22,54).…”

“…TLR4 receptors abolishes the inflammatory signaling response, indicating that activation of TLR4 by ethanol could be an important mechanism of ethanol-induced neuroinflammation (22).…”

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide

“…However, for the cases of alcohol and suffering from a psychiatric condition, the present study may not represent accurate interactions of these factors with the expression of cytokines. This limitation is relevant considering the reported effects of alcohol on inflammatory processes in the brain (49,50) and the association between cytokines and psychiatric diseases (40,41). Future studies matching controls and suicides for these factors, expanding the analysis to other brain regions, and including additional cytokines will be necessary to strengthen the evidence on the involvement of cytokines in suicide.…”