Inhibition of IRAK4 kinase activity improves ethanol-induced liver injury in mice.

Jul 20, 2020

Contributor: Han Wang,Hao Zhou,Quanri Zhang,Kyle L Poulsen,Vanessa Taylor,Megan R McMullen,Doug Czarnecki,Dhweeja Dasarathy,Minjia Yu,Yun Liao,Daniela S Allende,Xing Chen,Lingzi Hong,Junjie Zhao,Jinbo Yang,Laura E Nagy,Xiaoxia Li

Inhibition of IRAK4 kinase activity improves ethanol-induced liver injury in mice.

Alcohol-related liver disease (ALD) is a major cause of chronic liver disease worldwide with limited therapeutic options. Interleukin-1 Receptor Associated Kinase 4 (IRAK4), the master kinase of TLRs/IL-1R-mediated signaling activation, is considered a novel therapeutic target in inflammatory diseases, but has not been investigated in the context of ALD.
IRAK4 phosphorylation and IRAK1 protein were analyzed in liver from alcohol-related hepatitis patients and healthy controls. IRAK4 kinase activity-inactive knock-in (IRAK4 KI) mice and bone marrow chimeric mice were exposed to chronic ethanol-induced liver injury. IL-1β-induced IRAK4-mediated signaling and acute phase response were investigated in cultured hepatocytes. IRAK1/4 inhibitor was used to test the therapeutic potential for ethanol-induced liver injury in mice.
Increased IRAK4 phosphorylation and reduced IRAK1 protein were found in livers of alcoholic hepatitis patients. In the chronic ethanol-induced liver injury mouse model, hepatic inflammation and hepatocellular damage were attenuated in IRAK4 KI mice. IRAK4 kinase activity promotes expression of acute phase proteins in response to ethanol exposure, including C-reactive protein and serum amyloid A1(SAA1). SAA1 and IL-1β synergistically exacerbate ethanol-induced cell death ex vivo. Pharmacological blockage of IRAK4 kinase abrogated ethanol-induced liver injury, inflammation, steatosis, as well as acute phase gene expression and protein production in mice.
Our data elucidate the critical role of IRAK4 kinase activity in the pathogenesis of ethanol-induced liver injury in mice and provide pre-clinical validation for use of an IRAK1/4 inhibitor as a new potential therapeutic strategy for the treatment of ALD.

Copyright © 2020. Published by Elsevier B.V.

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About The Expert

Han Wang

School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China; Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Hao Zhou

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Quanri Zhang

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Kyle L Poulsen

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Vanessa Taylor

Rigel Pharmaceuticals, South San Francisco, CA 94080, USA.

Megan R McMullen

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Doug Czarnecki

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Dhweeja Dasarathy

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Harvard University, Massachusetts Hall, Cambridge, MA 02138, USA.

Minjia Yu

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, 02138, USA.

Yun Liao

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Daniela S Allende

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Pathology Department, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA;(;).

Xing Chen

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Lingzi Hong

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Junjie Zhao

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Jinbo Yang

School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China. Electronic address: yangjb@lzu.edu.cn.

Laura E Nagy

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: nagyl3@ccf.org.

Xiaoxia Li

Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: lix@ccf.org.

References

PubMed