TLR5 drives metabolic dysfunction-associated steatohepatitis through lipid- and flagellin-induced hepatocyte injury signalling

Abstract

Liver fibrosis is a strong predictor of clinical outcomes in metabolic dysfunction-associated steatohepatitis (MASH). Fibrosis is a consequence of persistent liver cell injury and inflammation in which Toll-like receptors (TLRs) play a key initiating role. Here we test the hypothesis that TLR5 is involved in the development of MASH and fibrosis using a combination of clinical data from multiple independent patient cohorts, single cell liver transcriptomics and human in vitro and ex vivo models. Hepatic TLR5 expression, but not TLR2 or TLR4, is associated with liver fibrosis and mortality. Plasma levels of TLR5s cognate ligand flagellin are increased in MASH with advanced fibrosis and fall with liver disease improvement. Mechanistically, we identify two parallel TLR5-mediated routes to hepatocyte injury: one elicited by flagellin and the other indirectly by lipid injury. Furthermore, hepatocyte TLR5 inhibition abrogates paracrine activation of hepatic stellate cells to suppress collagen production. This is also seen ex vivo in patient-derived precision-cut liver slices where TLR5 inhibition significantly reduces lipid-induced collagen deposition. These findings reveal a new role for TLR5 signalling, specifically in the development of advanced MASH fibrosis and may offer a novel disease-specific therapeutic approach.