Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in mice
Jun Xu, Hsiao-Yen Ma, Xiao Liu, Sara Rosenthal, Jacopo Baglieri, Ryan McCubbin, Mengxi Sun, Yukinori Koyama, Cedric G. Geoffroy, Kaoru Saijo, Linshan Shang, Takahiro Nishio, Igor Maricic, Max Kreifeldt, Praveen Kusumanchi, Amanda Roberts, Binhai Zheng, Vipin Kumar, Karsten Zengler, Donald P. Pizzo, Mojgan Hosseini, Candice Contet, Christopher K. Glass, Suthat Liangpunsakul, Hidekazu Tsukamoto, Bin Gao, Michael Karin, David A. Brenner, George F. Koob, Tatiana Kisseleva
Jun Xu, Hsiao-Yen Ma, Xiao Liu, Sara Rosenthal, Jacopo Baglieri, Ryan McCubbin, Mengxi Sun, Yukinori Koyama, Cedric G. Geoffroy, Kaoru Saijo, Linshan Shang, Takahiro Nishio, Igor Maricic, Max Kreifeldt, Praveen Kusumanchi, Amanda Roberts, Binhai Zheng, Vipin Kumar, Karsten Zengler, Donald P. Pizzo, Mojgan Hosseini, Candice Contet, Christopher K. Glass, Suthat Liangpunsakul, Hidekazu Tsukamoto, Bin Gao, Michael Karin, David A. Brenner, George F. Koob, Tatiana Kisseleva
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Research Article Gastroenterology

Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in mice

Abstract

Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients, and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL-17 receptor A (IL-17ra–/–) or pharmacological blockade of IL-17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL-17A positively correlated with the alcohol use in excessive drinkers and was further increased in patients with ALD as compared with healthy individuals. Our data suggest that IL-17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL-17A may provide a novel strategy for treatment of alcohol-induced pathology.

Authors

Jun Xu, Hsiao-Yen Ma, Xiao Liu, Sara Rosenthal, Jacopo Baglieri, Ryan McCubbin, Mengxi Sun, Yukinori Koyama, Cedric G. Geoffroy, Kaoru Saijo, Linshan Shang, Takahiro Nishio, Igor Maricic, Max Kreifeldt, Praveen Kusumanchi, Amanda Roberts, Binhai Zheng, Vipin Kumar, Karsten Zengler, Donald P. Pizzo, Mojgan Hosseini, Candice Contet, Christopher K. Glass, Suthat Liangpunsakul, Hidekazu Tsukamoto, Bin Gao, Michael Karin, David A. Brenner, George F. Koob, Tatiana Kisseleva

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Figure 2

IL-17ra–/– mice are protected from alcoholic liver fibrosis.

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IL-17ra–/– mice are protected from alcoholic liver fibrosis. WT and IL-1...
WT and IL-17ra–/– littermates (male C57BL/6, 12 weeks old) were pair-fed (n = 5–7/group) or IG alcohol fed (n = 7–10/group, 2 independent experiments). (A) Serum levels of ALT (IU/L) and EtOH (nM) were measured. (B) Livers were stained with H&E and Sirius Red, and positive area was calculated as percentage; micrographs are shown using ×20 objective. Expression of (C) fibrogenic and (D) inflammatory gene mRNA. Data are shown as fold change (vs. IG alcohol–fed WT mice). One-way ordinary ANOVA for multiple comparisons was applied. *P < 0.05; **P < 0.01 (see Supplemental Figure 3). Col1α1, collagen type 1 α1; α-SMA, α–smooth muscle actin; TIMP1, tissue inhibitor of metalloproteinase 1.