Our laboratory has been actively studying the pathogenesis of alcoholic liver disease, focusing on the role of miR-223 in alcoholic liver disease. MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47phox-oxidative stress pathway in neutrophils Objectives: Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant miRNAs in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice. Designs: Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by binging a single dose of ethanol. Results: Compared to healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of ALT and AST. MiRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared to healthy controls. In mice, chronic-plus-binge ethanol feeding elevated miR-223 in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS), and upregulated hepatic expression of IL-6 and phagocytic oxidase (phox) p47phox. Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47phox expression in neutrophils. Deletion of the p47phox gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47phox expression were upregulated in peripheral blood neutrophils from alcoholics compared to healthy controls. Conclusions MiR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease, and could be a novel therapeutic target for the treatment of this malady.
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