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 5

Serum levels of IL-17A are elevated in excessive drinkers and alcohol-dependent mice.

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Serum levels of IL-17A are elevated in excessive drinkers and alcohol-de...
(A) Serum levels of IL-17A cytokine were measured in excessive drinkers with normal ALT (<40 U/L, n = 21) or elevated ALT (≥40 U/L, n = 36) and healthy individuals (n = 18). Data are shown as IL-17A concentration, pg/mL, presented as mean ± SD. Two-way ordinary ANOVA. Patient information is summarized in Supplemental Tables 1 and 2. (B) Naive mice (male C57BL/6J, n = 4–6/experimental condition) were subjected to 2BC sessions to determine baseline voluntary ethanol drinking. Mice were then exposed to either Air (nondependent mice) or CIE (dependent mice). CIE produced an escalation of voluntary ethanol drinking during 2BC sessions conducted 3 to 7 days into withdrawal from vapor (vs. nondependent mice). Dependent and nondependent mice (n = 4–6/group) were treated with or without anti–IL-17A Ab, or with or without RORγt inhibitor, and (C) serum IL-17A was measured (after CIE or Air, withdrawal day 4, and 24 hours after 2BC-CIE; also see Supplemental Figure 11A). *P < 0.05.