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
Graphical Abstract
Keywords
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Article Info
Publication History
Published online: January 24, 2020
Accepted:
January 14,
2020
Received in revised form:
December 22,
2019
Received:
October 9,
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.
