Z Gastroenterol 2024; 62(01): e14-e15
DOI: 10.1055/s-0043-1777503
Abstracts | GASL
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A Mavs-induced type I IFN pathway contributes to non-viral liver injury upon hepatic autophagy impairment

Farina Schneider
1   Institute for Pathology, University Hospital of Cologne
,
Tom Lüdde
2   Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine University Hospital Düsseldorf, Germany
,
Manolis Pasparakis
3   Institute for Genetics and CECAD Research Center, University of Cologne
,
Evangelos Kondylis
4   Institute for Pathology, University Hospital of Cologne and Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine University Hospital Düsseldorf, Germany
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Hepatocellular injury drives the development of chronic inflammatory liver disease (CLD), such as alcoholic and metabolic dysfunction-associated steatohepatitis (ASH and MASH) and viral hepatitis, thereby predisposing to cirrhosis and hepatocarcinogenesis. Autophagy is an intracellular catabolic pathway that maintains cellular homeostasis serving as a prosurvival mechanism under physiological and stress conditions. Impaired autophagy has been associated with CLD pathogenesis in mouse models and patients with ASH and MASH.

We have used a genetic mouse model of liver parenchymal cell-specific autophagy impairment (ATG16L1 LPC-KO), which presents all typical phenotypic CLD characteristics, including spontaneous liver injury, hepatomegaly, hepatitis, fibrosis and eventually liver cancer. Similar to ASH and MASH patients, ATG16L1 LPC-KO mice show accumulation of cytoplasmic aggregates containing the autophagy receptor Sequestosome1/p62 in their hepatocytes. Through genetic means, we have confirmed previous studies showing that p62 partly contributes to liver injury and hepatocarcinogenesis in mice with hepatic autophagy impairment. To look for additional molecular pathways that that are relevant for hepatocellular injury in this model, we performed quantitative proteomics in livers from 8-week-old mice and our analysis revealed the upregulation of a Type I interferon (IFN) signature that was not normalized upon p62 ablation. Using genetic knockouts, we confirmed that engagement of Ifnar1 in LPCs significantly contributes to the observed liver injury, while IFN production is induced via a Mavs-dependent, but Sting-independent, pathway. The role of these Type I IFN pathway players in liver tumor development, as well as the contribution of IFN-induced and cell death regulating protein Zbp1, are currently investigated.



Publication History

Article published online:
23 January 2024

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