Han Wang1, Hao Zhou2, Quanri Zhang2, Kyle L Poulsen2, Vanessa Taylor3, Megan R McMullen2, Doug Czarnecki2, Dhweeja Dasarathy4, Minjia Yu5, Yun Liao6, Daniela S Allende7, Xing Chen6, Lingzi Hong6, Junjie Zhao6, Jinbo Yang8, Laura E Nagy9, Xiaoxia Li10. 1. 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. 2. 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. 3. Rigel Pharmaceuticals, South San Francisco, CA 94080, USA. 4. Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Harvard University, Massachusetts Hall, Cambridge, MA 02138, USA. 5. 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. 6. Inflammation and Immunity Department, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. 7. 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. 8. School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China. Electronic address: yangjb@lzu.edu.cn. 9. 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. 10. 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.
Abstract
BACKGROUNDS & AIMS: 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 Toll-like receptor (TLR)/IL-1R-mediated signalling activation, is considered a novel therapeutic target in inflammatory diseases, but has not been investigated in the context of ALD. METHODS: IRAK4 phosphorylation and IRAK1 protein were analysed 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 signalling 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. RESULTS: Increased IRAK4 phosphorylation and reduced IRAK1 protein were found in livers of patients with alcoholic hepatitis. 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. CONCLUSIONS: Our data elucidate the critical role of IRAK4 kinase activity in the pathogenesis of ethanol-induced liver injury in mice and provide preclinical validation for use of an IRAK1/4 inhibitor as a new potential therapeutic strategy for the treatment of ALD. LAY SUMMARY: Herein, we have identified the role of IRAK4 kinase activity in the development of alcohol-induced liver injury in mice. Hepatocyte-specific IRAK4 is associated with an acute phase response and release of proinflammatory cytokines/chemokines, which synergistically exacerbate alcohol-induced hepatocyte cell death ex vivo. Pharmacological inhibition of IRAK4 kinase activity effectively attenuates alcohol-induced liver injury in mice and could have therapeutic implications.
BACKGROUNDS & AIMS: 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 Toll-like receptor (TLR)/IL-1R-mediated signalling activation, is considered a novel therapeutic target in inflammatory diseases, but has not been investigated in the context of ALD. METHODS:IRAK4 phosphorylation and IRAK1 protein were analysed in liver from alcohol-related hepatitispatients 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 signalling 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. RESULTS: Increased IRAK4 phosphorylation and reduced IRAK1 protein were found in livers of patients with alcoholic hepatitis. In the chronic ethanol-induced liver injurymouse 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. CONCLUSIONS: Our data elucidate the critical role of IRAK4 kinase activity in the pathogenesis of ethanol-induced liver injury in mice and provide preclinical validation for use of an IRAK1/4 inhibitor as a new potential therapeutic strategy for the treatment of ALD. LAY SUMMARY: Herein, we have identified the role of IRAK4 kinase activity in the development of alcohol-induced liver injury in mice. Hepatocyte-specific IRAK4 is associated with an acute phase response and release of proinflammatory cytokines/chemokines, which synergistically exacerbate alcohol-induced hepatocyte cell death ex vivo. Pharmacological inhibition of IRAK4 kinase activity effectively attenuates alcohol-induced liver injury in mice and could have therapeutic implications.
Authors: Stephen R Atkinson; Karim Hamesch; Igor Spivak; Nurdan Guldiken; Joaquín Cabezas; Josepmaria Argemi; Igor Theurl; Heinz Zoller; Sheng Cao; Philippe Mathurin; Vijay H Shah; Christian Trautwein; Ramon Bataller; Mark R Thursz; Pavel Strnad Journal: Am J Gastroenterol Date: 2020-03 Impact factor: 10.864
Authors: T Matsusaka; K Fujikawa; Y Nishio; N Mukaida; K Matsushima; T Kishimoto; S Akira Journal: Proc Natl Acad Sci U S A Date: 1993-11-01 Impact factor: 11.205
Authors: Jorge Henao-Mejia; Eran Elinav; Chengcheng Jin; Liming Hao; Wajahat Z Mehal; Till Strowig; Christoph A Thaiss; Andrew L Kau; Stephanie C Eisenbarth; Michael J Jurczak; Joao-Paulo Camporez; Gerald I Shulman; Jeffrey I Gordon; Hal M Hoffman; Richard A Flavell Journal: Nature Date: 2012-02-01 Impact factor: 49.962