Impairment of Hematopoietic Precursor Cell Activation during the Granulopoietic Response to Bacteremia in Mice with Chronic-Plus-Binge Alcohol Administration.
*Alcohol; *bacteremia; *cell signaling; *granulocytes; *granulopoietic response; *stem cells; Animal; Animals; Antigens; Bacteremia/genetics/*immunology/pathology; Binge Drinking/genetics/*immunology/pathology; Bone Marrow Cells/drug effects/immunology/pathology; CCAAT-Enhancer-Binding Protein-beta/genetics/immunology; Cyclin D1/genetics/immunology; Disease Models; Escherichia coli Infections/genetics/*immunology/pathology; Escherichia coli/growth & development/immunology; Ethanol/*pharmacology; Gene Expression Regulation/*drug effects/immunology; Granulocytes/drug effects/immunology/pathology; Hematopoiesis/*drug effects/genetics/immunology; Inbred BALB C; Ly/genetics/immunology; Male; Membrane Proteins/genetics/immunology; Mice; Mitogen-Activated Protein Kinase 1/genetics/immunology; Mitogen-Activated Protein Kinase 3/genetics/immunology; Nucleotidyltransferases/deficiency/genetics/immunology; Proto-Oncogene Proteins c-kit/genetics/immunology; Signal Transduction/*drug effects/immunology; Toll-Like Receptor 4/genetics/immunology
Alcohol abuse impairs immune defense. To study the effect of chronic-plus-binge alcohol exposure on the granulopoietic response, acute alcohol intoxication (intraperitoneal injection of 5 g alcohol/kg body weight) was introduced to mice chronically fed on the Lieber-DeCarli low-fat liquid alcohol diet for 5 weeks. Bacteremia was induced by intravenous injection of Escherichia coli Bacteremia caused a remarkable increase in marrow lin(-) c-kit(+) Sca-1(+) cells. Activation of cell proliferation supported the increase in marrow lin(-) c-kit(+) Sca-1(+) cells. Alcohol administration inhibited this activation of lin(-) c-kit(+) Sca-1(+) cells. The bone marrow of pair-fed control mice receiving intraperitoneal saline stored a large number of mature granulocytes expressing a high level of Gr1 (Gr1(hi) cells). The proportion of Gr1(hi) cells and the total number of Gr1(+) cells were markedly reduced in the bone marrow, along with an increase in the ratio of Gr1(+) granulocytes in peripheral white blood cells following bacteremia. E. coli infection stimulated proliferation of granulopoietic precursor cells, resulting in a marked increase in the ratio of immature Gr1(lo) cells in the bone marrow. Alcohol administration itself triggered marrow release of Gr1(+) cells, resulting in reduction of the marrow granulocyte reserve with an elevation of granulocytes in the circulation. Alcohol also impaired activation of granulopoietic precursor proliferation following bacteremia. Alcohol disrupted lipopolysaccharide (LPS)-TLR4-ERK1/2-cyclin D1 signaling and inhibited upregulation of Sca-1 and C/EBPbeta expression by lineage-negative marrow cells in response to bacteremia. These results indicate that chronic-plus-binge alcohol exposure inhibits the granulopoietic response by disrupting key cell signaling for hematopoietic precursor cell activation and commitment to granulocyte lineage development.
Shi Xin; Lin Yuan-Ping; Gao Bin; Zhang Ping
Infection and immunity
2017
2017-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1128/IAI.00369-17" target="_blank" rel="noreferrer noopener">10.1128/IAI.00369-17</a>
MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the
*CYTOKINES; *ETHANOL; *FATTY LIVER; *INFLAMMATION; *LEUKOCYTES; Adult; Alanine Transaminase/blood; Alcoholic/genetics/*metabolism/pathology; Alcoholism/*blood/complications; Animals; Aspartate Aminotransferases/blood; Bilirubin/blood; Binge Drinking/*blood/complications; Case-Control Studies; Central Nervous System Depressants/administration & dosage; Down-Regulation; Ethanol/administration & dosage; Female; Humans; Inbred C57BL; Interleukin-6/genetics/metabolism; Liver Diseases; Male; Mice; MicroRNAs/*blood/*genetics; Middle Aged; NADPH Oxidases/genetics/metabolism; Neutrophils/*metabolism; Reactive Oxygen Species/metabolism; Up-Regulation; Young Adult
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.
Li Man; He Yong; Zhou Zhou; Ramirez Teresa; Gao Yueqiu; Gao Yanhang; Ross Ruth A; Cao Haixia; Cai Yan; Xu Ming-Jiang; Feng Dechun; Zhang Ping; Liangpunsakul Suthat; Gao Bin
Gut
2017
2017-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1136/gutjnl-2016-311861" target="_blank" rel="noreferrer noopener">10.1136/gutjnl-2016-311861</a>
The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice.
Alcoholic/*metabolism; Animal; Animals; Blotting; Disease Models; Fatty Liver; Humans; Inbred C57BL; Knockout; Lipocalin-2/*metabolism; Mice; Polymerase Chain Reaction; Western
We have previously shown that the ethanol-mediated elevation of lipocaline-2 (LCN2) is closely associated with the development of alcoholic fatty liver disease (AFLD) in mice. Herein, we aimed to understand the functional significance of LCN2 induction by ethanol and to explore its underlying mechanisms. We evaluated the effects of LCN2 in an in vitro cellular alcoholic steatosis model and in an animal study using wild-type and LCN2 knockout mice fed for 4 weeks with an ethanol-supplemented Lieber-DeCarli diet. In the cellular model of alcoholic steatosis, recombinant LCN2 or overexpression of LCN2 exacerbated ethanol-induced fat accumulation, whereas knocking down LCN2 prevented steatosis in hepatocytes exposed to ethanol. Consistently, removal of LCN2 partially but significantly alleviated alcoholic fatty liver injury in mice. Mechanistically, LCN2 mediates detrimental effects of ethanol in the liver via disrupted multiple signaling pathways, including aberrant nicotinamide phosphoribosyltransferase-sirtuin 1 axis, perturbed endocrine metabolic regulatory fibroblast growth factor 15/19 signaling, and impaired chaperone-mediated autophagy. Finally, compared with healthy human livers, liver samples from patients with AFLD had lower gene expression of several
Cai Yan; Jogasuria Alvin; Yin Huquan; Xu Ming-Jiang; Hu Xudong; Wang Jiayou; Kim Chunki; Wu Jiashin; Lee Kwangwon; Gao Bin; You Min
The American journal of pathology
2016
2016-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ajpath.2016.05.006" target="_blank" rel="noreferrer noopener">10.1016/j.ajpath.2016.05.006</a>