TLR4 and CD14 as potential therapeutic targets for LPS-induced acute-on-chronic liver failure

Acute-on-chronic liver failure (ACLF) is characterized by rapid decompensation of liver functions as a result of acute insult in patients with pre-existing chronic liver disease. The lack of mouse models successfully recapitulating the human ACLF hinders the efforts to understand the underlying mechanism and to identify therapeutic options. In order to bridge this gap and to better understand the event cascade leading to the hepatic decompensation, a mouse model for ACLF was established. First, metabolic dysfunction–associated steatotic liver disease (MASLD) was induced by feeding mice on Western-style diet for 48 weeks. MASLD was characterized by extensive hepatic alterations, including bridging fibrosis, immune cell infiltration, and elevated liver enzymes. Next, MASLD mice were challenged with lipopolysaccharide (LPS) as an acute insult. Similarly to the human ACLF, the MASLD mice were more susceptible to LPS than age-matched standard diet fed mice, leading to aggravated cytokine storm and multi-organ failure. Interestingly, some components of the LPS internalization machinery, such as CD14 and Tlr4, were found to be upregulated in the MASLD mice. To understand their relevance in the increased susceptibility to LPS, MASLD mice were pre-treated with Tlr4 and CD14 inhibitors 30 minutes before LPS administration. Inhibiting these targets strongly attenuated the inflammatory cytokine response to LPS and increased the mouse survival rate. In conclusion, blocking Tlr4 and CD14 strongly ameliorated the effect of LPS in mice with advanced MASLD, and could be a promising therapeutic target for human ACLF.

Publication History

Article published online:
20 January 2025