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Published on: July 26, 2017
Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure
Cornelius Engelmann1, Mohammed Sheikh2, Shreya Sharma2
1Liver 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.
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.
Insights
Inhibiting Toll-like receptor 4 (TLR4) signaling with TAK-242 significantly reduces organ injury and inflammation in rodent models of acute and acute-on-chronic liver failure, improving survival and suggesting therapeutic potential.
Area of Science:
- Hepatology
- Immunology
- Pharmacology
Background:
- Toll-like receptor 4 (TLR4) is crucial in mediating organ damage in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF).
- Elevated TLR4 ligands and hepatic TLR4 expression are observed in patients with cirrhosis.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting TLR4 signaling in ALF and ACLF.
- To assess the efficacy of the TLR4 inhibitor TAK-242 in preclinical models of liver failure.
Main Methods:
- Rodent models of ACLF and ALF were established using bile duct ligation or carbon tetrachloride, followed by lipopolysaccharide (LPS) administration.
- TAK-242 was administered in vivo to assess effects on survival, organ injury, and cytokine levels.
- In vitro studies on human monocytes and hepatocytes evaluated TAK-242's impact on cytokine secretion and cell death.
Main Results:
- TAK-242 reduced LPS-induced cytokine secretion and cell death in vitro.
- In ACLF models, TAK-242 improved survival, decreased liver and kidney cell death, and lowered circulating cytokine levels.
- In ALF models, TAK-242 prevented organ injury and systemic inflammation.
Conclusions:
- TLR4 signaling is a key driver of liver injury in both ALF and ACLF.
- Inhibition of TLR4 with TAK-242 ameliorates organ damage and improves outcomes in preclinical models.
- TAK-242 demonstrates significant therapeutic potential for patients suffering from liver failure.
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