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

Engelmann, C; Sheikh, M; Sharma, S; Kondo, T; Loeffler-Wirth, H; Zheng, YB; Novelli, S; ... Jalan, R; + view all (2020) Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure. Journal of Hepatology , 73 (1) pp. 102-112. 10.1016/j.jhep.2020.01.011. Green open access

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Abstract

Background and 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). Here we assess whether inhibiting TLR4 signaling can ameliorate liver failure and serve as a potential treatment. / Material and Methods: Circulating TLR4 ligands and hepatic TLR4 expression was measured in plasma samples and liver biopsies from patients with cirrhosis. TAK-242 (TLR4 inhibitor) was tested in vivo with 10mg/Kg, i.p. in rodent models of ACLF (bile duct ligation + lipopolysaccharide (LPS); carbontetrachloride + 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 IL6, IL1b 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 liver p<0.001) and kidneys (p=0.048) and reduced circulating cytokine levels (IL1b p<0.001). In a rodent model of ALF TAK-242 prevented organ injury (p<0.001) and systemic inflammation (IL1b p<0.001). / Conclusion: This study shows that TLR4 signaling is a key factor in the development of both ACLF and ALF and its inhibition improves severity of organ injury and outcome. TAK-242 may be of therapeutic relevance in patients with liver failure.

Type: Article
Title: Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jhep.2020.01.011
Publisher version: https://doi.org/10.1016/j.jhep.2020.01.011
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: ACLF, ALF, DAMP, LPS, PAMP, TLR4, inflammation, lipopolysaccharide, liver injury
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Education
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: https://discovery.ucl.ac.uk/id/eprint/10090850
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