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2017 ; 66
(4
): 705-715
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MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the
IL-6-p47(phox)-oxidative stress pathway in neutrophils
#MMPMID27679493
Li M
; He Y
; Zhou Z
; Ramirez T
; Gao Y
; Gao Y
; Ross RA
; Cao H
; Cai Y
; Xu M
; Feng D
; Zhang P
; Liangpunsakul S
; Gao B
Gut
2017[Apr]; 66
(4
): 705-715
PMID27679493
show ga
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 microRNAs (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 a single binge of ethanol. RESULTS: Compared with healthy controls or
alcoholics without recent drinking, alcoholics with recent excessive drinking had
higher levels of circulating neutrophils, which correlated with serum levels of
alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis
revealed that alcoholics had elevated serum miR-223 levels compared with healthy
controls. In chronic-plus-binge ethanol feeding mouse model, the levels of
miR-223 were increased 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 interleukin
(IL)-6 and phagocytic oxidase (phox) p47(phox). Mechanistic studies revealed that
miR-223 directly inhibited IL-6 expression and subsequently inhibited p47(phox)
expression in neutrophils. Deletion of the p47(phox) gene ameliorated
ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223
expression was downregulated, while IL-6 and p47(phox) expression were
upregulated in peripheral blood neutrophils from alcoholics compared with 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.
|Adult
[MESH]
|Alanine Transaminase/blood
[MESH]
|Alcoholism/*blood/complications
[MESH]
|Animals
[MESH]
|Aspartate Aminotransferases/blood
[MESH]
|Bilirubin/blood
[MESH]
|Binge Drinking/*blood/complications
[MESH]
|Case-Control Studies
[MESH]
|Central Nervous System Depressants/administration & dosage
[MESH]
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