Highlights
- •IRAK4 kinase activity is required for ethanol-induced liver injury in mice.
- •Hepatocyte-specific IRAK4 is associated with acute-phase protein release in response to interleukin-1β.
- •Acute phase response and proinflammatory cytokine/chemokines synergistically exacerbate ethanol-induced cell death ex vivo.
- •Pharmacological inhibition of IRAK4 kinase activity attenuates ethanol-induced liver injury in mice.
- •Targeting IRAK4 kinase activity might be a potential therapeutic strategy for the treatment of alcohol-associated liver disease.
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.
Graphical abstract
Graphical Abstract
Keywords
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References
- Global Status Report on Alcohol and Health.WHO, Geneva2014
- Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585
- Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.Hepatology. 2015; 62: 762-772
- Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.Gut. 2011; 60: 255-260
- Bidirectional communication between liver and gut during alcoholic liver disease.Semin Liver Dis. 2016; 36: 331-339
- Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice.Hepatology. 2001; 34: 101-108
- Redox signaling and the innate immune system in alcoholic liver disease.Antioxid Redox Signal. 2011; 15: 523-534
- Toll-like receptors in liver disease.Adv Clin Chem. 2013; 59: 155-201
- Interleukin-1 and the pathogenesis of the acute-phase response.N Engl J Med. 1984; 311: 1413-1418
- Effect of alcohol consumption on systemic markers of inflammation.Lancet. 2001; 357: 763-767
- C-reactive protein is a biomarker of AFP-negative HBV-related hepatocellular carcinoma.Int J Oncol. 2015; 47: 543-554
- Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.J Clin Invest. 2009; 119: 305-314
- Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.Nature. 2012; 482: 179-185
- TLR4 enhances TGF-beta signaling and hepatic fibrosis.Nat Med. 2007; 13: 1324-1332
- Dendritic cells in hepatitis C infection: can they (help) win the battle?.J Gastroenterol. 2011; 46: 432-447
- Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling.Nature. 2010; 465: 885
- TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent.J Biol Chem. 2006; 281: 21013-21021
- IRAK4 in TLR/IL-1R signaling: possible clinical applications.Eur J Immunol. 2008; 38: 614-618
- β-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from the membrane to the cytosol for TAK1-dependent NFκB activation.Mol Cell Biol. 2012; 32: 3990-4000
- A critical role for IRAK4 kinase activity in toll-like receptor-mediated innate immunity.J Exp Med. 2007; 204: 1025-1036
- The critical role of IL-1 receptor-associated kinase 4-mediated NF-kappaB activation in modified low-density lipoprotein-induced inflammatory gene expression and atherosclerosis.J Immunol. 2011; 186: 2871-2880
- Deficiency in IRAK4 activity attenuates manifestations of murine lupus.Eur J Immunol. 2017; 47: 880-891
- Selective IRAK4 inhibition attenuates disease in murine lupus models and demonstrates steroid sparing activity.J Immunol. 2017; 198: 1308-1319
- Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy.J Exp Med. 2015; 212: 2189-2201
- Targeting myddosome signaling in Waldenström's macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191.Clin Cancer Res. 2018; 24: 6408-6420
- IRAKM-Mincle axis links cell death to inflammation: pathophysiological implications for chronic alcoholic liver disease.Hepatology. 2016; 64: 1978-1993
- Mouse model of chronic and binge ethanol feeding (the NIAAA model).Nat Protoc. 2013; 8: 627-637
- Monocyte activation in alcoholic liver disease.Alcohol. 2002; 27: 53-61
- Acute-phase proteins and other systemic responses to inflammation.N Engl J Med. 1999; 340: 448-454
- Hepatocytes as immunological agents.J Immunol. 2016; 196: 17-21
- A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family.EMBO J. 1990; 9: 1897-1906
- Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.Proc Natl Acad Sci U S A. 1993; 90: 10193-10197
- Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes.J Lipid Res. 2005; 46: 2497-2505
- IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice.J Clin Invest. 2012; 122: 3476-3489
- Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation.Mol Biol Med. 1990; 7: 147-159
Markovtsov V.V., Lamagna C., Chan M., Yi S., Young C., Frances R., et al. Potential role for R191, potent and selective IRAK4 kinase inhibitor, in treatment of hematologic malignancies. AACR 2016.
- Serum amyloid A induces inflammation, proliferation and cell death in activated hepatic stellate cells.PLoS One. 2016; 11: e0150893
- Neutrophil-mediated tissue injury in alcoholic hepatitis.Alcohol. 2002; 27: 23-27
- Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: a critical role for E-selectin.Hepatology. 2013; 58: 1814-1823
- Treatment of alcohol use disorder in patients with alcoholic liver disease.Am J Med. 2017; 130: 124-134
- Dual effect of ethanol on cell death in primary culture of human and rat hepatocytes.Alcohol Alcohol. 2004; 39: 290-296
- Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation.J Hepatol. 2018; 68: 986-995
- A validated score predicts acute kidney injury and survival in patients with alcoholic hepatitis: a multicentric international prospective cohort study.Liver Transpl. 2018; 24: 1655-1664
- Myeloid-MyD88 contributes to ethanol-induced liver injury in mice linking hepatocellular death to inflammation.Alcohol Clin Exp Res. 2017; 41: 719-726
- Inflammasome activation and function in liver disease.Nat Rev Gastroenterol Hepatol. 2015; 12: 387-400
- Prognostic value of C-reactive protein levels in patients with cirrhosis.Liver Transpl. 2015; 21: 753-760
- Serum transferrin is an independent predictor of mortality in severe alcoholic hepatitis.Am J Gastroenterol. 2020; 115: 398-405
Article Info
Publication History
Published online: July 15, 2020
Accepted:
July 7,
2020
Received in revised form:
July 3,
2020
Received:
May 24,
2019
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
