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. PizzoMojgan Hosseini, Candice Contet, Christopher K. Glass, Suthat Liangpunsakul, Hidekazu Tsukamoto, Bin Gao, Michael Karin, David A. Brenner, George F. Koob, Tatiana Kisseleva

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere131277
JournalJCI Insight
Volume5
Issue number3
DOIs
StatePublished - Feb 13 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by NIH grants R01 DK101737-01A1, U01 AA022614-01A1, R01 DK099205-01A1, P50AA011999, and AI043477 to TK and DAB; AI043477 to MK; NS093055 and NS054734 to BZ; R01 CA 100660 and R01 AA020864 to VK; R21AA024935, R01 DK107682, and R01 AA025208 to SL; and R21 AA024198, P60 AA006420, and R01 AA021491 to CC. Further support was received from the Herman Lopata Memorial Hepatitis Postdoctoral ALF Fellowship (to JX), 1I01CX000361 from the Veterans Affairs Research and Administration (to SL), W81XWH-12-1-0497 from the US Department of Defense, and the Showalter Scholar Award from the Ralph W. and Grace M. Showalter Research Trust (to SL).

Publisher Copyright:
© 2020, American Society for Clinical Investigation.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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