Question:
Increased translocation of intestinal bacteria is a pathological hallmark in patients
with chronic liver disease (CLD). Thereby, Toll-like Receptor (TLR) signaling, stimulated
by bacterial products, derived from intestinal microbiota, trigger inflammation driving
inititation and progression of CLD and hepatocellular carcinoma (HCC). In the current
study, the role of MyD88 in parenchymal and non-parenchymal cells in the development
of fibrosis and tumour initiation and progression was studied in a murine model of
inflammation triggered HCC development.
Methods:
To explore the impact of Myd88 for hepatitis, fibrogenesis and HCC formation, B6-MyD88-/- mice or alternatively hepatocyte-specific B6-MyD88-/-(MyD88Δhepa) were crossed with hepatocyte-specific NEMO knockout mice (NEMOΔhepa) to generate NEMOΔhepa/MyD88-/- or NEMOΔhepa/MyD88Δhepa mice respectively.
Results:
Unexpected, hepatocyte specific MyD88 deletion in NEMOΔhepa mice did not alter the course of CLD as well as changes in HCC initiation and progression.
In contrast, constitutional deletion of MyD88 aggravated CLD in NEMOΔhepa mice as characterized by elevated serum alanine (ALT), aspartate serum transaminases
(AST) as well as glutamate dehydrogenase (GLDH) values. Histopathological examination
of H&E stained liver tissue confirmed increased liver injury in NEMOΔhepa/MyD88-/- compared with NEMOΔhepa mice which was associated with a mild increase of apoptosis. this finding was associated
with a significant increase in monocyte-derived macrophages and a significant reduction
in CD4 T cells in NEMOΔhepa/MyD88-/- livers. Furthermore, TNFα and MCP1 was reduced in NEMOΔhepa/MyD88-/- livers compared to NEMOΔhepa livers.
52 weeks old NEMOΔhepa/MyD88-/- mice had a lower cumulative tumour burden as well as reduced tumour size in comparison
with NEMOΔhepa tumours. These findings were accompanied by a decrease in serum level transaminases
likewise a reduction in liver body weight ratio. In line with this data, histological
examination by two blinded pathologists revealed that the non-neoplastic and neoplastic
phenotypes of the NEMOΔhepa livers were rescued by the concomitant constitutional deletion of MyD88 as indicated
by a lower total lesions burden score and tumor incidence.
Conclusion:
Deletion of MyD88 in non-parenchymal, but not in parenchymal cells in NEMOΔhepa mice leads to an accelerated onset of chronic liver disease but reduces the neoplastic
potential as evidenced by reduced HCC initiation and progression. These results indicate
that MyD88 in non-parenchymal cells might be an attractive target to treat the treatment
of chronic liver disease.
