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

Abstract

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.

• Authors: Cornelius Engelmann, Mohammed Sheikh, Shreya Sharma, Takayuki Kondo, Henry Loeffler-Wirth, Yu Bao Zheng, Simone Novelli, Andrew Hall, Annarein J C Kerbert, Jane Macnaughtan, Rajeshwar Mookerjee, Abeba Habtesion, Nathan Davies, Tauhid Ali, Saurabh Gupta, Fausto Andreola, Rajiv Jalan
• Journal: Journal of hepatology (J Hepatol) Vol. 73 Issue 1 Pg. 102-112 (07 2020) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 31987990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Interleukin-1beta
• Ligands
• Sulfonamides
• TLR4 protein, human
• Toll-Like Receptor 4
• ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate

Topics

• Acute-On-Chronic Liver Failure (etiology, metabolism, prevention & control)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Gene Expression Profiling
• Hepatocytes (metabolism)
• Humans
• Interleukin-1beta (analysis)
• Ligands
• Liver Cirrhosis (blood, drug therapy, metabolism, pathology)
• Liver Failure, Acute (etiology, metabolism, prevention & control)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• THP-1 Cells
• Toll-Like Receptor 4 (antagonists & inhibitors, metabolism)
• Treatment Outcome