Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in LdIr(-/-) Mice

Mike L. J. Jeurissen, Sofie M. A. Walenbergh, Tom Houben, Tim Hendrikx, Jieyi Li, Yvonne Oligschläger, Patrick J. van Gorp, Marion J. J. Gijbels, Albert Bitorina, Isabell Nessel, Freddy Radtke, Marc Vooijs, Jan Theys, Ronit Shiri-Sverdlov*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Web of Science)

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by liver steatosis and inflammation. Currently, the underlying mechanisms leading to hepatic inflammation are not fully understood and consequently, therapeutic options are poor. Non-alcoholic steatohepatitis (NASH) and atherosclerosis share the same etiology whereby macrophages play a key role in disease progression. Macrophage function can be modulated via activation of receptor-ligand binding of Notch signaling. Relevantly, global inhibition of Notch ligand Delta-Like Ligand-4 (DLL4) attenuates atherosclerosis by altering the macrophage-mediated inflammatory response. However, the specific contribution of macrophage DLL4 to hepatic inflammation is currently unknown. We hypothesized that myeloid DLL4 deficiency in low-density lipoprotein receptor knock-out (LdIr(-/-) mice reduces hepatic inflammation. Irradiated LdIr(-/-) mice were transplanted (tp) with bone marrow from wild type (Wt) or DLL4(f/f)LysMCre(+0) (DLL4(del)) mice and fed either chow or high fat, high cholesterol (HFC) diet for 11 weeks. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) of DLL4(f/f)LysM-Cre(WT) and DLL(f/f)LysMCre(+/0) mice. In contrast to our hypothesis, inflammation was not decreased in HFC-fed DLL4(del)-transplanted mice. In line, in vitro, there was no difference in the expression of inflammatory genes between DLL4-deficient and wildtype bone marrow derived macrophages. These results suggest that myeloid DLL4 deficiency does not contribute to hepatic inflammation in vivo. Since, macrophage-DLL4 expression in our model was not completely suppressed, it can't be totally excluded that complete DLL4 deletion in macrophages might lead to different results. Nevertheless, the contribution of non-myeloid Kupffer cells to notch signaling with regard to the pathogenesis of steatohepatitis is unknown and as such it is possible that, DLL4 on Kupffer cells promote the pathogenesis of steatohepatitis.
Original languageEnglish
Article numbere0167199
JournalPLOS ONE
Volume11
Issue number11
DOIs
Publication statusPublished - 29 Nov 2016

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