TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain

Abstract

New evidence indicates the involvement of protein degradation dysfunctions in neurodegeneration, innate immunity response and alcohol hepatotoxicity. We recently demonstrated that ethanol increases brain proinflammatory mediators and causes brain damage by activating Toll-like receptor 4 (TLR4) signaling in glia. However, it is uncertain if the ubiquitin-proteasome and autophagy-lysosome pathways are involved in ethanol-induced brain damage and whether the TLR4 response is implicated in proteolytic processes. Using the cerebral cortex of WT and TLR4-knockout mice with and without chronic ethanol treatment, we demonstrate that ethanol induces poly-ubiquitinated proteins accumulation and promotes immunoproteasome activation by inducing the expression of β2i, β5i and PA28α, although it decreases the 20S constitutive proteasome subunits (α2, β5). Ethanol also upregulates mTOR phosphorylation, leading to a downregulation of the autophagy-lysosome pathway (ATG12, ATG5, cathepsin B, p62, LC3) and alters the volume of autophagic vacuoles. Notably, mice lacking TLR4 receptors are protected against ethanol-induced alterations in protein degradation pathways. In summary, the present results provide the first evidence demonstrating that chronic ethanol treatment causes proteolysis dysfunctions in the mouse cerebral cortex and that these events are TLR4 dependent. These findings could provide insight into the mechanisms underlying ethanol-induced brain damage.

Cocaine-mediated microglial activation involves the ER stress-autophagy axis

“…48 Intriguingly, autophagy has also been implicated to play a neuroprotective role in the context of alcohol 49 and is shown to involve TLR-mediated pathways. 50 Additionally, cannabinoids also induce autophagy in human glioma cells. 29 Our findings for the first time suggest that yet another drug, cocaine can induce autophagy in microglial cells.…”

Autophagy and ethanol neurotoxicity

“…However, chronic ethanol exposure in adult mice activates MTOR and causes impairment of the autophagy-lysosome pathway in the brain. 46 This implies that long-term exposure to ethanol may damage this protective system and further jeopardize CNS neurons to subsequent ethanol exposure and other insults. In turn, this finding suggests that upregulation of autophagy may be beneficial not only for the damage caused by acute ethanol exposure in the developing brain but also for deficits in the adult brain induced by chronic exposure.…”

“…46 The mechanisms of ethanol inhibition of MTORC1 are unclear. Ethanol induces ROS production and affects several upstream kinases of MTORC1, such as PI3K-AKT and GSK3B in neurons.…”

Chronic Binge Alcohol Administration Dysregulates Hippocampal Genes Involved in Immunity and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques

“…This CBA-specific up-regulation is potentially due to increased immunoproteasome activity. Supporting this interpretation, chronic alcohol administration increases the expression of immunoproteasome subunits and catalytic activity in brain tissue [28]. Furthermore, using this same model of CBA and SIV infection, we previously reported that proteasome subunit expression is dysregulated and proteasome activity is increased in skeletal muscle of CBA/SIV+ macaques [11].…”