Ethanol Inhibits Activation Of Nlrp3 And Aim2 Inflammasomes In Human Macrophages- A Novel Anti-Inflammatory Action Of Alcohol

Objective: In the pathogenesis of coronary atherosclerosis, local macrophage-driven inflammation and secretion of proinflammatory cytokines, interleukin-1 beta (IL-1 beta) in particular, are recognized as key factors. Moderate alcohol consumption is associated with a reduced risk of coronary artery disease mortality. Here we examined in cultured human macrophages whether ethanol modulates the intracellular processes involved in the secretion of IL-1 beta.Results: Ethanol decreased dose-dependently the production of mature IL-1b induced by activators of the NLRP3 inflammasome, i.e. ATP, cholesterol crystals, serum amyloid A and nigericin. Ethanol had no significant effect on the expression of NLRP3 or IL1 beta mRNA in LPS-primed macrophages. Moreover, secretion of IL-1 beta was decreased in parallel with reduction of caspase-1 activation, demonstrating that ethanol inhibits inflammasome activation instead of synthesis of pro-IL-1 beta. Acetaldehyde, a highly reactive metabolite of ethanol, had no effect on the ATP-induced IL-1 beta secretion. Ethanol also attenuated the secretion of IL-1 beta triggered by synthetic double-stranded DNA, an activator of the AIM2 inflammasome. Ethanol conferred the inhibitory functions by attenuating the disruption of lysosomal integrity and ensuing leakage of the lysosomal protease cathepsin B and by reducing oligomerization of ASC.Conclusion: Ethanol-induced inhibition of the NLRP3 inflammasome activation in macrophages may represent a biological pathway underlying the protective effect of moderate alcohol consumption on coronary heart disease.