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Background/Aims: Alcohol consumption has been shown to cause neuroinflammation and increase a variety of immune-related signaling processes. Microglia are a crucial part of alcohol-induced neuroinflammation and undergo apoptosis. Even though the importance of these inflammatory processes in the effects of alcohol-related neurodegeneration have been established, the mechanism of alcohol-induced microglia apoptosis is unknown. In prior research, we discovered that alcohol increases expression of salt-inducible kinase 1 (SIK1) in rodent brain tissue. In this study, we sought to determine what role SIK1 expression plays in alcohol-induced neuroinflammation as well as whether and by what mechanism it regulates microglia apoptosis. Methods: Adult C57BL/6 mice were divided into four groups and for 3 weeks treated with either 0%, 5%, 10%, or 15% alcohol during 3 hour periods. The mice were sacrificed and their brains excised for analysis. Additionally, primary microglia were isolated from neonatal mice. SIK1 expression in alcohol-treated brain tissue and microglia was analyzed via RT-PCR and western blotting. TUNEL staining, caspase-3, and caspase-9 activity assays were performed to evaluate microglial apoptosis. Cell fluorescence staining and NF-κB luciferase activity assays were used to evaluate the effects of SIK1 expression on the NF-κB signaling pathway. Results:SIK1 expression was increased in the brains of mice that consumed alcohol, and this effect was seen in mouse primary microglia. SIK1 knockdown in microglia increased alcohol-induced apoptosis in these cells. Furthermore, SIK1 reduced NF-κB signaling pathway factors, and SIK1 knockdown in microglia promoted alcohol-induced NF-κB activity. TUNEL staining, caspase-3, and caspase-9 activity assays consistently revealed that alcohol-induced microglial apoptosis was inhibited by depletion of p65. Finally, we determined that NF-κB signaling is required for alcohol-induced, SIK1-mediated apoptosis in microglia. Conclusion: This study establishes for the first time not only that SIK1 is crucial to regulating alcohol-induced microglial apoptosis, but also that the NF-κB signaling pathway is required for its activity. Overall, our results help elucidate mechanisms of alcohol-induced neuroinflammation. [ABSTRACT FROM AUTHOR]