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Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure

  • Author Footnotes
    ‡ Both authors share first authorship.
    Cornelius Engelmann
    Footnotes
    ‡ Both authors share first authorship.
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom

    Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany

    Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charite - Universitätsmedizin Berlin, Germany
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  • Author Footnotes
    ‡ Both authors share first authorship.
    Mohammed Sheikh
    Footnotes
    ‡ Both authors share first authorship.
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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  • Shreya Sharma
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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  • Takayuki Kondo
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom

    Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • Henry Loeffler-Wirth
    Affiliations
    Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany
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  • Yu Bao Zheng
    Affiliations
    Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, China
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  • Simone Novelli
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom

    Department of Mechanical and Aerospace Engineering, Sapienza University of Rome, Rome, Italy
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  • Andrew Hall
    Affiliations
    Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, United Kingdom
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  • Annarein J.C. Kerbert
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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  • Jane Macnaughtan
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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  • Rajeshwar Mookerjee
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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  • Abeba Habtesion
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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  • Nathan Davies
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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  • Tauhid Ali
    Affiliations
    Takeda Pharmaceuticals International Co, Cambridge, United States of America
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  • Saurabh Gupta
    Affiliations
    Takeda Pharmaceuticals International Co, Cambridge, United States of America
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  • Author Footnotes
    # Both authors share senior authorship.
    Fausto Andreola
    Footnotes
    # Both authors share senior authorship.
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
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  • Author Footnotes
    # Both authors share senior authorship.
    Rajiv Jalan
    Correspondence
    Corresponding author. Address: Liver Failure Group, Institute for Liver & Digestive Health, Division of Medicine, University College London UCL, Rowland Hill Street, London, NW3 2PF, United Kingdom. Tel.: +44 02074332795.
    Footnotes
    # Both authors share senior authorship.
    Affiliations
    Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
    Search for articles by this author
  • Author Footnotes
    ‡ Both authors share first authorship.
    # Both authors share senior authorship.
Published:January 24, 2020DOI:https://doi.org/10.1016/j.jhep.2020.01.011

      Highlights

      • Cirrhosis is associated with TLR4-related sensitization to endotoxins and a switch from apoptotic to necroptotic cell death.
      • Inhibition of TLR4 signaling by TAK-242 reduces immune cell responses and hepatocyte injury in response to LPS in vitro.
      • In models of acute and acute-on-chronic liver failure, TAK-242 mitigated LPS-driven systemic inflammation and organ injury.

      Background & Aims

      Toll-like receptor 4 (TLR4) plays an essential role in mediating organ injury in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Herein, we assess whether inhibiting TLR4 signaling can ameliorate liver failure and serve as a potential treatment.

      Methods

      Circulating TLR4 ligands and hepatic TLR4 expression were measured in plasma samples and liver biopsies from patients with cirrhosis. TAK-242 (TLR4 inhibitor) was tested in vivo (10 mg/kg intraperitoneally) in rodent models of ACLF (bile duct ligation + lipopolysaccharide [LPS]; carbon tetrachloride + LPS) and ALF (galactosamine + LPS) and in vitro on immortalized human monocytes (THP-1) and hepatocytes (HHL5). The in vivo therapeutic effect was assessed by coma-free survival, organ injury and cytokine release and in vitro by measuring IL-6, IL-1β or cell injury (TUNEL), respectively.

      Results

      In patients with cirrhosis, hepatic TLR4 expression was upregulated and circulating TLR4 ligands were increased (p <0.001). ACLF in rodents was associated with a switch from apoptotic cell death in ALF to non-apoptotic forms of cell death. TAK-242 reduced LPS-induced cytokine secretion and cell death (p = 0.002) in hepatocytes and monocytes in vitro. In rodent models of ACLF, TAK-242 administration improved coma-free survival, reduced the degree of hepatocyte cell death in the liver (p <0.001) and kidneys (p = 0.048) and reduced circulating cytokine levels (IL-1β, p <0.001). In a rodent model of ALF, TAK-242 prevented organ injury (p <0.001) and systemic inflammation (IL-1β, p <0.001).

      Conclusion

      This study shows that TLR4 signaling is a key factor in the development of both ACLF and ALF; its inhibition reduces the severity of organ injury and improves outcome. TAK-242 may be of therapeutic relevance in patients with liver failure.

      Lay summary

      Toll-like receptor 4 (or TLR4) mediates endotoxin-induced tissue injury in liver failure and cirrhosis. This receptor sensitizes cells to endotoxins, which are produced by gram-negative bacteria. Thus, inhibiting TLR4 signaling with an inhibitor (TAK-242) ameliorates organ injury and systemic inflammation in rodent models of acute and acute-on-chronic liver failure.

      Graphical abstract

      Keywords

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