MyD88-dependent signaling in non-parenchymal cells promotes liver carcinogenesis

Antje Mohs, Nadine Kuttkat, Tobias Otto, Sameh A. Youssef, Alain de Bruin, Christian Trautwein*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    2 Citations (Scopus)

    Abstract

    In Western countries, a rising incidence of obesity and type 2 diabetes correlates with an increase of non-Alcoholic steatohepatitis (NASH)-A major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). NASH is associated with chronic liver injury, triggering hepatocyte death and enhanced translocation of intestinal bacteria, leading to persistent liver inflammation through activation of Toll-like receptors and their adapter protein myeloid differentiation factor 88 (MyD88). Therefore, we investigated the role of MyD88 during progression from NASH to HCC using a mouse model of chronic liver injury (hepatocyte-specific deletion of nuclear factor ?B essential modulator, Nemo; Nemo?hepa). Nemo?hepa; Nemo?hepa/MyD88-/- and Nemo?hepa/MyD88?hepa were generated and the impact on liver disease progression was investigated. Ubiquitous MyD88 ablation (Nemo?hepa/MyD88-/-) aggravated the degree of liver damage, accompanied by an overall decrease in inflammation, whereas infiltrating macrophages and natural killer cells were elevated. At a later stage, MyD88 deficiency impaired HCC formation. In contrast, hepatocyte-specific MyD88 deletion (Nemo?hepa/MyD88?hepa) did not affect disease progression. These results suggest that signaling of Toll-like receptors through MyD88 in non-parenchymal liver cells is required for carcinogenesis during chronic liver injury. Hence, blocking MyD88 signaling may offer a therapeutic option to prevent HCC formation in patients with NASH.

    Original languageEnglish
    Pages (from-to)171-181
    Number of pages11
    JournalCARCINOGENESIS
    Volume41
    Issue number2
    DOIs
    Publication statusPublished - Feb-2020

    Keywords

    • TOLL-LIKE RECEPTORS
    • NF-KAPPA-B
    • NEMO/IKK-GAMMA
    • CANCER
    • STEATOHEPATITIS
    • TUMORIGENESIS
    • INFLAMMATION
    • EXPRESSION
    • IMMUNITY
    • ACTIVATION

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