Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression

Zhe Shen, Yan Liu, Bedair Dewidar, Junhao Hu, Ogyi Park, Teng Feng, Chengfu Xu, Chaohui Yu, Qi Li, Christoph Meyer, Iryna Ilkavets, Alexandra Müller, Carolin Stump-Guthier, Stefan Munker, Roman Liebe, Vincent Zimmer, Frank Lammert, Peter R. Mertens, Hai Li, Peter ten DijkeHellmut G. Augustin, Jun Li, Bin Gao, Matthias P. Ebert, Steven Dooley, Youming Li, Hong Lei Weng

Research output: Contribution to journalArticle

Abstract

Disrupting Notch signaling ameliorates experimental liver fibrosis. However, the role of individual Notch ligands in liver damage is unknown. We investigated the effects of Delta-like ligand 4 (Dll4) in liver disease. DLL4 expression was measured in 31 human liver tissues by immunohistochemistry. Dll4 function was examined in carbon tetrachloride– and bile duct ligation–challenged mouse models in vivo and evaluated in hepatic stellate cells, hepatocytes, and Kupffer cells in vitro. DLL4 was expressed in patients' Kupffer and liver sinusoidal endothelial cells. Recombinant Dll4 protein (rDll4) ameliorated hepatocyte apoptosis, inflammation, and fibrosis in mice after carbon tetrachloride challenge. In vitro, rDll4 significantly decreased lipopolysaccharide-dependent chemokine expression in both Kupffer and hepatic stellate cells. In bile duct ligation mice, rDll4 induced massive hepatic necrosis, resulting in the death of all animals within 1 week. Inflammatory cell infiltration and chemokine ligand 2 (Ccl2) expression were significantly reduced in rDll4-receiving bile duct ligation mice. Recombinant Ccl2 rescued bile duct ligation mice from rDll4-mediated death. In patients with acute-on-chronic liver failure, DLL4 expression was inversely associated with CCL2 abundance. Mechanistically, Dll4 regulated Ccl2 expression via NF-κB. Taken together, Dll4 modulates liver inflammatory response by down-regulating chemokine expression. rDll4 application results in opposing outcomes in two models of liver damage. Loss of DLL4 may be associated with CCL2-mediated cytokine storm in patients with acute-on-chronic liver failure.

Original languageEnglish (US)
Pages (from-to)1874-1889
Number of pages16
JournalAmerican Journal of Pathology
Volume186
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Shen, Z., Liu, Y., Dewidar, B., Hu, J., Park, O., Feng, T., Xu, C., Yu, C., Li, Q., Meyer, C., Ilkavets, I., Müller, A., Stump-Guthier, C., Munker, S., Liebe, R., Zimmer, V., Lammert, F., Mertens, P. R., Li, H., ... Weng, H. L. (2016). Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression. American Journal of Pathology, 186(7), 1874-1889. https://doi.org/10.1016/j.ajpath.2016.03.010