Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612767
Poster Visit Session IV Tumors, Liver Surgery and Transplantation – Saturday, January 27, 2018, 8:30am – 9:15am, Foyer area West Wing
Georg Thieme Verlag KG Stuttgart · New York

Deletion of MyD88 in non-parenchymal cells, but not in parenchymal cells attenuates the progression of hepatocellular carcinoma

A Mohs
1   University Hospital, RWTH Aachen, Germany, Department of Internal Medicine III, Aachen
,
N Kuttkat
1   University Hospital, RWTH Aachen, Germany, Department of Internal Medicine III, Aachen
,
T Otto
1   University Hospital, RWTH Aachen, Germany, Department of Internal Medicine III, Aachen
,
R Sonntag
1   University Hospital, RWTH Aachen, Germany, Department of Internal Medicine III, Aachen
,
S Youssef
2   Utrecht University, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht
,
A de Bruin
2   Utrecht University, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht
3   University of Groningen, University Medical Centre Groningen, Department of Paediatrics, Groningen
,
C Trautwein
1   University Hospital, RWTH Aachen, Germany, Department of Internal Medicine III, Aachen
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2018 (online)

Also available at
 

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.