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DOI: 10.1055/s-0037-1605073
Jagged-1 expression in stressed hepatocytes enhances phagocytic activity of Kupffer cells
Publication History
Publication Date:
02 August 2017 (online)
Introduction:
Reactive oxygen species (ROS) are drivers of pathogenesis for liver diseases through lipid peroxidation, DNA hydroxylation, and protein adduct formation. Further, ROS can activate Nrf2 to induce antioxidant enzymes. Nrf2 also regulates Notch1 signaling, therewith impacting liver regeneration. Here, we report Notch ligand Jagged-1 (Jag-1) as inducible target of ROS in hepatocytes.
Methods:
Jag-1 expression was examined in animal models associated with ROS generation, in mouse hepatocytes upon treatment with APAP and CCl4, and HBV and primary biliary cirrhosis (PBC) patients presenting with ROS generation, using qPCR, immunoblot and IHC. Involvement of Nrf2 was investigated through co-IF staining for Jag-1 and Nrf2 target SOD2. Functionally, a role for Jag-1 in phagocytosis was studied in co-cultures of Kupffer cells pre-treated with recombinant Jag-1 (rJag-1) and labeled hepatocyte debris.
Results:
Jag-1 was expressed in hepatocytes adjacent to necrotic area following CCl4 and APAP administration to mice. APAP/CCl4 induced Jag-1 expression in cultured mouse hepatocytes. Hepatocytes of HBV and PBC patients show high Jag-1 expression compared to normal liver. Jag-1 protein co-localized with SOD-2. Interestingly, Kupffer cells pretreated with rJag-1 showed enhanced phagocytic activity, whereas the Γ-Secretase/Notch Inhibitor Dibenzazepine blunted phagocytosis. During cholestasis and intoxication with APAP, some hepatocytes accumulate intracellular bile salts. To test whether Jag-1 expression in stressed hepatocytes may be caused by high intracellular bile salt concentrations cultured mouse hepatocytes were incubated with CDCA, which caused a concentration dependent increase in Jag-1, Nrf2 and HO-1, suggesting that increased bile salt concentrations may initiate Jag-1 mediated mechanisms.
Conclusion:
Bile salts induced Jag-1 expression in ROS-stressed hepatocytes, probably via an Nrf2-dependent mechanism. Jag-1 expression then may function as DAMP to induce phagocytic activity of infiltrating Kupffer cells to clear dead hepatocytes efficiently and enhance liver regeneration.