Taken together, our observations emphasize that a disturbance in the cellular housekeeping, induced by alcohol exposure, can trigger the pro-inflammatory sensor NLRP3, therefore stimulating inflammatory reactions in pluripotent stem cells as well as NPCs. Evidence indicates that multiple factors play a role in the alcohol-mediated response, such as Heat Shock Factor 1 [53], mTOR [54, 55], or TLR4 [6]. Though a linear cascade of events has not yet been determined due to the concurrence of multiple cross-talking mechanisms, we have illustrated that an impairment of mitochondrial and lysosomal distribution and function are involved in ethanol-mediated induction of the inflammasome pathway, resulting in a disequilibrium of the innate immune response and metabolism. Moreover, we also conclude that ethanol differentially enhances the vulnerability of either pluripotent or neural progenitor cells to further challenge through the involvement of the NLRP3 inflammasome pathway that acts as a sensor of cell metabolism and that finally regulates cell survival and differentiation. A better understanding of neuronal metabolism shows promise in providing novel therapeutic avenues to tackle ethanol neurotoxicity. The iPS cell model represents an invaluable tool both for the identification of pathogenic mechanisms and for drug screening in human cells.
